How changes in depression severity and borderline personality disorder intensity are linked - a cohort study of depressed patients with and without borderline personality disorder.

BACKGROUND: Borderline personality disorder (BPD) is often complicated by comorbid major depressive episodes (MDEs), which can occur as part of major depressive disorder (MDD) or bipolar disorder (BD). Such comorbidity is related to worse outcomes in both disorders. Subsyndromal features of BPD are also common in depression. However, studies of simultaneous changes in BPD and depression severities are scarce, and their interactions are poorly understood. AIMS: Studying the associations between changes in BPD and depression symptoms over the course of an MDE. METHODS: In a 6-month naturalistic cohort study of MDE/BPD, MDE/MDD, and MDE/BD patients (N = 95), we measured change in BPD features between baseline and six months with the Borderline Personality Disorder Severity Index (BPDSI), an interviewer-rated instrument quantifying recent temporal frequency of BPD symptoms. We examined changes in BPD severity and their correlation with depression severity and other clinical measures and compared these across patient groups. RESULTS: There were significant reductions in BPD severity, both in number of positive BPD criteria (-0.35, sd 1.38, p = 0.01672) and in BPDSI scores (-4.23, SD 6.74, p < 0.001), reflecting mainly a reduction in temporal frequency of symptoms. These were similar in all diagnostic groups. In multivariate regression models, changes in depression severity independently associated with changes in symptoms in the BDSI. This relationship was strongest in MDE/BPD patients but was not found in MDD patients without BPD. CONCLUSIONS: In the six-month follow-up, BPD features in MDE patients alleviated mainly by decreasing temporal symptom frequency and intensity. In BPD patients with comorbid MDE, changes in both conditions are strongly correlated.

Affect dimensions and variability during major depressive episodes: Ecological momentary assessment of unipolar, bipolar, and borderline patients and healthy controls.

Differentiating major depressive episodes (MDEs) of major depressive disorder (MDD), bipolar disorder (MDE/BD) and the MDEs comorbid with borderline personality disorder (MDE/BPD) is crucial for appropriate treatment, and knowledge of phenomenological differences may aid this. However, studies comparing affect experiences of these three patient groups and healthy subjects are scarce. In our study, participants (N = 114), including patients with MDD (n = 34), MDE/BD (n = 27), and MDE/BPD (n = 24), and healthy controls (HC, n = 29) responded to ecological momentary assessment (EMA) with ten circumplex model affect items ten times daily for seven days (7709 recordings). Explorative factor analysis resulted in two affect dimensions. The positive dimension included active, excited, cheerful (high arousal), and content (low arousal) affects, and the negative dimension irritated, angry, and nervous (high arousal) affects. Relative to HC, patients reported 3.5-fold negative affects (mean MDD 1.36 (SD 0.92), MDE/BD 1.43 (0.76), MDE/BPD 1.81 (0.95) vs. HC 0.44 (0.49) (p < 0.01)) but 0.5-fold positive affects (2.01 (0.90), 1.95 (0.89), 2.24 (1.03), vs. 3.2 (0.95), respectively (p < 0.01)). We used multilevel modelling. Negative-affect within-individual stability was lowest in MDE/BPD and highest in MDD. Negative affect predicted concurrent positive affect more in MDE/BPD than in MDD. Moderate size of subcohorts and no inpatients were limitations. Despite apparently similar MDEs, affective experiences may differ between BPD, BD, and MDD patients. Clinical subgroups of patients with depression may vary in affective instability and concurrent presence of negative and positive affects during depression.

Borderline personality disorder and depression severity predict suicidal outcomes: A six-month prospective cohort study of depression, bipolar depression, and borderline personality disorder.

BACKGROUND: Suicide risk is high in patients with major depressive disorder (MDD), bipolar disorder (BD) and borderline personality disorder (BPD). Whether risk levels of and risk factors for suicidal ideation (SI) and suicide attempts (SA) are similar or different in these disorders remains unclear, as few directly comparative studies exist. The relationship of short-term changes in depression severity and SI is underinvestigated, and might differ across groups, for example, between BPD and non-BPD patients. METHODS: We followed, for 6 months, a cohort of treatment-seeking, major depressive episode (MDE) patients in psychiatric care (original n = 124), stratified into MDE/MDD, MDE/BD and MDE/BPD subcohorts. We examined risks of suicide-related outcomes and their risk factors prospectively. We examined the covariation of SI and depression over time with biweekly online modified Patient Health Questionnaire 9 surveys and analysed this relationship through multi-level modelling. RESULTS: Risk of SA in BPD (22.2%) was higher than non-BPD (4.23%) patients. In regression models, BPD severity was correlated with risk of SA and clinically significant SI. During follow-up, mean depression severity and changes in depression symptoms were associated with SI risk regardless of diagnosis. CONCLUSIONS: Concurrent BPD in depression seems predictive for high risk of SA. Severity of BPD features is relevant for assessing risk of SA and SI in MDE. Changes in depressive symptoms indicate concurrent changes in risk of SI. BPD status at intake can index risk for future SA, whereas depressive symptoms appear a useful continuously monitored risk index.

Relationship between daily rated depression symptom severity and the retrospective self-report on PHQ-9: A prospective ecological momentary assessment study on 80 psychiatric outpatients.

BACKGROUND: Depression-related negative bias in emotional processing and memory may bias accuracy of recall of temporally distal symptoms. We tested the hypothesis that when responding to the Patient Health Questionnaire (PHQ-9) the responses reflect more accurately temporally proximal than distal mood states. METHODS: Currently, depressed psychiatric outpatients (N = 80) with depression confirmed in semi-structured interviews had the Aware application installed on their smartphones for ecological momentary assessment (EMA). The severity of "low mood", "hopelessness", "low energy", "anhedonia", and "wish to die" was assessed on a Likert scale five times daily during a 12-day period, and thereafter, the PHQ-9 questionnaire was completed. We used auto- and cross-correlation analyses and linear mixed-effects multilevel models (LMM) to investigate the effect of time lag on the association between EMA of depression symptoms and the PHQ-9. RESULTS: Autocorrelations of the EMA of depressive symptom severity at two subsequent days were strong (r varying from 0.7 to 0.9; p < 0.001). "Low mood" was the least and "wish to die" the most temporally stable symptom. The correlations between EMA of depressive symptoms and total scores of the PHQ-9 were temporally stable (r from 0.3 to 0.6; p < 0.001). No effect of assessment time on the association between EMA data and the PHQ-9 emerged in the LMM. LIMITATIONS: Altogether 11.5 % of observations were missing. CONCLUSIONS: Despite fluctuations in severity of some of the depressive symptoms, patients with depression accurately recollect their most dominant symptoms, without a significant recall bias favouring the most recent days, when responding to the PHQ-9.

Finnish Psychotherapy Quality Register: rationale, development, and baseline results.

BACKGROUND: The push to systematically follow treatment outcomes in psychotherapies to improve health care is increasing worldwide. To manage psychotherapeutic services and facilitate tailoring of therapy according to feedback a comprehensive and feasible data system is needed. AIMS: To describe the Finnish Psychotherapy Quality Register (FPQR), a comprehensive database on availability, quality, and outcomes of psychotherapies. METHODS: We describe the development of the FPQR and outcome for outsourced psychotherapies for adults in Helsinki and Uusimaa hospital district (HUS). Symptom severity and functioning are measured with validated measures (e.g. CORE-OM, PHQ-9, OASIS, AUDIT, and SOFAS). Questionnaires on therapeutic alliance, risks, methods, and goals are gathered from patients and psychotherapist. RESULTS: During 2018-2021, the FPQR included baseline data for 7274 unique patients and 336 psychotherapists. Response rate of measures was 85-98%. The use of the register was mandatory for the outsourced therapist of the hospital districts, and the patients were strongly recommended to fulfill the questionnaires. We report outcome for three groups of patients (n = 1844) with final/midterm data. The effect sizes for long psychotherapy (Hedge's g = 0.65 of SOFAS) were smaller than those for short psychotherapy (g = 0.75-0.91). Within three months of referral, 26-60% entered treatment depending on short- or long-term therapy. CONCLUSION: The FPQR forms a novel rich database with commensurate data on availability and outcomes of outsourced psychotherapies. It may serve as a basis for a national comprehensive follow-up system of psychosocial treatments. The Finnish system seems to refer patients with milder symptoms to more intensive treatments and achieve poorer results compared to the IAPT model in UK, Norway, or Australia.

Bipolar disorder predicted shorter and borderline personality disorder symptoms longer time to remission - A prospective cohort study of major depressive patients.

BACKGROUND: Major depressive episodes (MDEs) of major depressive (MDD) or bipolar disorders (BD) are frequently complicated by features of borderline personality disorder (BPD). Mixed features are a hallmark of BD and affective lability of BPD, and both may markedly influence illness course. However, direct comparisons of outcome of depression in MDD, BD, and BPD are scarce. METHODS: In a cohort study based on stratified sampling, we diagnosed psychiatric MDE patients with SCID-I/P and SCID-II interviews and examined mixed symptoms using the Mix-MDE scale and borderline symptoms using the Borderline Personality Disorder Severity Index. During a six-month prospective follow-up, the MDE patients with MDD (n = 39), BD (n = 33), or BPD (n = 23) completed biweekly online assessments. Using life chart methodology, we divided the follow-up period into qualitatively different mood state periods. We investigated durations of mood episodes, times to first full symptomatic remission, and their predictors. RESULTS: Remission rates were similar in MDD, MDE/BD, and MDE/BPD patients. MDE/BD patients experienced more numerous and shorter distinct mood state periods during follow-up than the others. MDE/BD was associated with shorter (HR = 2.44, 95 % CI = 1.27-4.67) and dimensionally assessed BPD severity with longer time to first remission (HR = 0.95, 95 % CI = 0.91-1.00). LIMITATIONS: Moderate sample size and follow-up duration. CONCLUSIONS: Course of illness over six months differs between the three depressive groups. Bipolar depressive patients have the most alternating course and the shortest time to first period of remission. Dimensionally assessed severity of BPD may predict longer time to remission from depression.

Escitalopram enhances synchrony of brain responses during emotional narratives in patients with major depressive disorder.

One-week treatment with escitalopram decreases amygdala responses to fearful facial expressions in depressed patients, but it remains unknown whether it also modulates processing of complex and freely processed emotional stimuli resembling daily life emotional situations. Inter-subject correlation (ISC) offers a means to track brain activity during complex, dynamic stimuli in a model-free manner. Twenty-nine treatment-seeking patients with major depressive disorder were randomized in a double-blind study design to receive either escitalopram or placebo for one week, after which functional magnetic resonance imaging (fMRI) was performed. During fMRI the participants listened to spoken emotional narratives. Level of ISC between the escitalopram and the placebo group was compared across all the narratives and separately for the episodes with positive and negative valence. Across all the narratives, the escitalopram group had higher ISC in the default mode network of the brain as well as in the fronto-temporal narrative processing regions, whereas lower ISC was seen in the middle temporal cortex, hippocampus and occipital cortex. Escitalopram increased ISC during positive parts of the narratives in the precuneus, medial prefrontal cortex, anterior cingulate and fronto-insular cortex, whereas there was no significant synchronization in brain responses to positive vs negative events in the placebo group. Increased ISC may imply improved emotional synchronization with others, particularly during observation of positive events. Further studies are needed to test whether this contributes to the later therapeutic effect of escitalopram.

Reduced visual contrast suppression during major depressive episodes.

Background: Previous studies have suggested that processing of visual contrast information could be altered in major depressive disorder. To clarify the changes at different levels of the visual hierarchy, we behaviourally measured contrast perception in 2 centre-surround conditions, assessing retinal and cortical processing. Methods: As part of a prospective cohort study, our sample consisted of controls (n = 29; 21 female) and patients with unipolar depression, bipolar disorder and borderline personality disorder who had baseline major depressive episodes (n = 111; 74 female). In a brightness induction test that assessed retinal processing, participants compared the perceived luminance of uniform patches (presented on a computer screen) as the luminance of the backgrounds was varied. In a contrast suppression test that assessed cortical processing, participants compared the perceived contrast of gratings, which were presented with collinearly or orthogonally oriented backgrounds. Results: Brightness induction was similar for patients with major depressive episodes and controls (p = 0.60, d = 0.115, Bayes factor = 3.9), but contrast suppression was significantly lower for patients than for controls (p < 0.006, d = 0.663, Bayes factor = 35.2). We observed no statistically significant associations between contrast suppression and age, sex, or medication or diagnostic subgroup. At follow-up (n = 74), we observed some normalization of contrast perception. Limitations: We assessed contrast perception using behavioural tests instead of electrophysiology. Conclusion: The reduced contrast suppression we observed may have been caused by decreased retinal feedforward or cortical feedback signals. Because we observed intact brightness induction, our results suggest normal retinal but altered cortical processing of visual contrast during a major depressive episode. This alteration is likely to be present in multiple types of depression and to partially normalize upon remission.

Presence and Overlap of Bipolar Symptoms and Borderline Features during Major Depressive Episodes.

BACKGROUND: Bipolar symptoms and borderline personality features occur in both unipolar and bipolar major depressive episodes (MDEs). We investigated their prevalence, severity, co-occurrence and overlap. METHODS: We interviewed 124 psychiatric outpatients with MDE using the Structured Clinical Interview for DSM-IV-TR Axis I and II Disorders, the Borderline Personality Disorder Severity Index (BPDSI-IV), and about past (hypo)manic episodes, and stratified them according to the principal diagnosis into subcohorts of major depressive disorder (MDD, n = 50), bipolar disorder (BD, n = 43), and borderline personality disorder (BPD, n = 31). We quantified (hypo)manic symptoms using a novel semi-structured interview (MIXed symptoms during MDE, MIX-MDE) with good psychometric qualities. RESULTS: The subcohorts did not differ in MDE severity. They differed significantly in some (hypo)manic symptoms being present on most days in 24% of MDD, 30% of BD, and 42% of BPD subcohort, but only 5% of the BD subcohort fulfilled the DSM-5 mixed features. The mean MIX-MDE scores were 5.7 (SD 4.0), 12.0 (8.2) and 10.5 (7.5), and BPDSI-IV scores 15.6 (7.0), 17.2 (6.2) and 26.9 (8.7), respectively (both p < 0.001). (Hypo)manic days and unspecific symptoms of distractibility and irritability inflated the correlation of observed (hypo)manic symptoms and borderline features. LIMITATIONS: Moderate sample size, limited age variation (18-50 years); no previous validation of MIX-MDE. CONCLUSIONS: Presence of some mixed and borderline features is common in MDEs, with overlap and diagnosis-specific differences. Unspecific symptoms of irritability and distractibility and the aggravating impact of hypomania on perceived BPD features blur the differential diagnosis.

Borderline Personality Disorder With Depression Confers Significant Risk of Suicidal Behavior in Mood Disorder Patients-A Comparative Study.

OBJECTIVE: We investigated risk factors for suicidal ideation and behavior among currently depressed patients with major depressive disorder (MDD), major depressive episode (MDE) in bipolar disorder (BD), or MDE with comorbid borderline personality disorder (MDE/BPD). We compared current and lifetime prevalence of suicidal ideation and behavior, and investigated dimensional measures of BPD or mixed affective features of the MDE as indicators of risk. METHODS: Based on screening of 1,655 referrals, we recruited 124 psychiatric secondary care outpatients with MDE and stratified them into three subcohorts (MDD, BD, and MDE/BPD) using the Structured Clinical Interview for DSM-IV I and II. We examined suicidal ideation and behavior with the Columbia Suicide Severity Rating Scale (CSSRS). In addition, we quantified the severity of BPD symptoms and BD mixed features both categorically/diagnostically and dimensionally (using instruments such as the Borderline Personality Disorder Severity Index) in two time frames. RESULTS: There were highly significant differences between the lifetime prevalences of suicide attempts between the subcohorts, with attempts reported by 16% of the MDD, 30% of the BD, and 60% of the BPD subcohort. Remarkably, the lifetime prevalence of suicide attempts in patients with comorbid BD and BPD exceeded 90%. The severity of BPD features was independently associated with risk of suicide attempts both lifetime and during the current MDE. It also associated in a dose-dependent manner with recent severity of ideation in both BPD and non-BPD patients. In multinominal logistic regression models, hopelessness was the most consistent independent risk factor for severe suicidal ideation in both time frames, whereas younger age and more severe BPD features were most consistently associated with suicide attempts. CONCLUSIONS: Among patients with major depressive episodes, diagnosis of bipolar disorder, or presence of comorbid borderline personality features both imply remarkably high risk of suicide attempts. Risk factors for suicidal ideation and suicidal acts overlap, but may not be identical. The estimated severity of borderline personality features seems to associate with history of suicidal behavior and current severity of suicidal ideation in dose-dependent fashion among all mood disorder patients. Therefore, reliable assessment of borderline features may advance the evaluation of suicide risk.

Short-term escitalopram treatment normalizes aberrant self-referential processing in major depressive disorder.

BACKGROUND: Increased self-focus and negative self-concept play an important role in depression. Antidepressants influence self-referential processing in healthy volunteers, but their function in self-processing of depressed patients remains unknown. METHODS: Thirty-two depressed patients were randomly allocated to receive either escitalopram 10 mg or placebo for one week. After one week, neural responses to positive and negative self-referential adjectives and neutral control stimuli were assessed with functional magnetic resonance imaging. A group of matched healthy volunteers served as a control group. RESULTS: Escitalopram decreased responses of medial fronto-parietal regions to self-referential words relative to non-emotional control stimuli, driven by increased responses to the control condition. Escitalopram also increased responses in the pre-defined region of the medial prefrontal cortex (MPFC) and the anterior cingulate cortex (ACC) to positive relative to negative words. Importantly, the changes in neural responses occurred before any effect on depressive symptoms, implying a direct effect of escitalopram. Furthermore, the placebo group had decreased responses of the MPFC and the ACC to positive self-referential processing relative to the matched healthy controls. However, neural responses of the escitalopram group and the healthy unmedicated controls were similar. LIMITATIONS: Differences between the groups in self-reported depression symptoms and personality traits may have influenced the results. CONCLUSION: One-week treatment with escitalopram normalized aberrant self-referential processing in depressed patients, shifting the focus from the self to the external environment and potentiating positive self-referential processing. This may be an important factor in mechanism of action of antidepressants.

Genome-Wide Association Study of Psychosis Proneness in the Finnish Population.

The current study examined quantitative measures of psychosis proneness in a nonpsychotic population, in order to elucidate their underlying genetic architecture and to observe if there is any commonality to that already detected in the studies of individuals with overt psychotic conditions, such as schizophrenia and bipolar disorder. Heritability, univariate and multivariate genome-wide association (GWAs) tests, including a series of comprehensive gene-based association analyses, were developed in 4269 nonpsychotic persons participating in the Northern Finland Birth Cohort 1966 study with information on the following psychometric measures: Hypomanic Personality, Perceptual Aberration, Physical and Social Anhedonia (also known as Chapman's Schizotypia scales), and Schizoidia scale. Genome-wide genetic data was available for ~9.84 million SNPs. Heritability estimates ranged from 16% to 27%. Phenotypic, genetic and environmental correlations ranged from 0.04-0.43, 0.25-0.73, and 0.12-0.43, respectively. Univariate GWAs tests revealed an intronic SNP (rs12449097) at the TMC7 gene (16p12.3) that significantly associated (P = 3.485 × 10-8) with the hypomanic scale. Bivariate GWAs tests including the hypomanic and physical anhedonia scales suggested a further borderline significant SNP (rs188320715; P-value = 5.261 × 10-8, ~572 kb downstream the ARID1B gene at 6q25.3). Gene-based tests highlighted 20 additional genes of which 5 had previously been associated to schizophrenia and/or bipolar disorder: CSMD1, CCDC141, SLC1A2, CACNA1C, and SNAP25. Altogether the findings explained from 3.7% to 14.1% of the corresponding trait heritability. In conclusion, this study provides preliminary genomic evidence suggesting that qualitatively similar biological factors may underlie different psychosis proneness measures, some of which could further predispose to schizophrenia and bipolar disorder.

Single dose of mirtazapine modulates whole-brain functional connectivity during emotional narrative processing.

The link between neurotransmitter-level effects of antidepressants and their clinical effect remain poorly understood. A single dose of mirtazapine decreases limbic responses to fearful faces in healthy subjects, but it is unknown whether this effect applies to complex emotional situations and dynamic connectivity between brain regions. Thirty healthy volunteers listened to spoken emotional narratives during functional magnetic resonance imaging (fMRI). In an open-label design, 15 subjects received 15mg of mirtazapine two hours prior to fMRI while 15 subjects served as a control group. We assessed the effects of mirtazapine on regional neural responses and dynamic functional connectivity associated with valence and arousal. Mirtazapine attenuated responses to unpleasant events in the right fronto-insular cortex, while modulating responses to arousing events in the core limbic regions and the cortical midline structures (CMS). Mirtazapine decreased responses to unpleasant and arousing events in sensorimotor areas and the anterior CMS implicated in self-referential processing and formation of subjective feelings. Mirtazapine increased functional connectivity associated with positive valence in the CMS and limbic regions. Mirtazapine triggers large-scale changes in regional responses and functional connectivity during naturalistic, emotional stimuli. These span limbic, sensorimotor, and midline brain structures, and may be relevant to the clinical effectiveness of mirtazapine.

A single dose of mirtazapine attenuates neural responses to self-referential processing.

Increased self-focus is a core factor in the psychopathology of depression. Cortical midline structures (CMS) are implicated in the neurobiology of self, depression and antidepressant treatment response. Mirtazapine, an antidepressant that increases serotonin and norepinephrine release, enhances processing of positive and attenuates processing of negative emotional information in healthy volunteers after a single dose. These early changes, which are opposite to the negative information bias in depression, may be important for the therapeutic effect of mirtazapine. It nevertheless remains unresolved whether/how mirtazapine specifically influences processing of self-referential emotional information.Half of the healthy volunteers (n=15/30) received a single dose of mirtazapine, in an open-label design, two hours before functional magnetic resonance imaging (fMRI), and the other half was scanned as a control group without medication. During fMRI the participants categorized positive and negative self-referential adjectives.Mirtazapine attenuated responses to self-referential processing in the medial prefrontal cortex and the anterior cingulate cortex. Mirtazapine further decreased responses to positive self-referential processing in the posterior cingulate cortex and parietal cortex.These decreased responses of the CMS suggest that mirtazapine may rapidly improve the ability of the CMS to down-regulate self-referential processing. In depressed patients, this could lead to decreased self-focus and rumination, contributing to the antidepressant effect.

The effect of personality on daily life emotional processes.

Personality features are associated with individual differences in daily emotional life, such as negative and positive affectivity, affect variability and affect reactivity. The existing literature is somewhat mixed and inconclusive about the nature of these associations. The aim of this study was to shed light on what personality features represent in daily life by investigating the effect of the Five Factor traits on different daily emotional processes using an ecologically valid method. The Experience Sampling Method was used to collect repeated reports of daily affect and experiences from 104 healthy university students during one week of their normal lives. Personality traits of the Five Factor model were assessed using NEO Five Factor Inventory. Hierarchical linear modeling was used to analyze the effect of the personality traits on daily emotional processes. Neuroticism predicted higher negative and lower positive affect, higher affect variability, more negative subjective evaluations of daily incidents, and higher reactivity to stressors. Conscientiousness, by contrast, predicted lower average level, variability, and reactivity of negative affect. Agreeableness was associated with higher positive and lower negative affect, lower variability of sadness, and more positive subjective evaluations of daily incidents. Extraversion predicted higher positive affect and more positive subjective evaluations of daily activities. Openness had no effect on average level of affect, but predicted higher reactivity to daily stressors. The results show that the personality features independently predict different aspects of daily emotional processes. Neuroticism was associated with all of the processes. Identifying these processes can help us to better understand individual differences in daily emotional life.

Neuropeptide precursor VGF is genetically associated with social anhedonia and underrepresented in the brain of major mental illness: its downregulation by DISC1.

In a large Scottish pedigree, disruption of the gene coding for DISC1 clearly segregates with major depression, schizophrenia and related mental conditions. Thus, study of DISC1 may provide a clue to understand the biology of major mental illness. A neuropeptide precursor VGF has potent antidepressant effects and has been reportedly associated with bipolar disorder. Here we show that DISC1 knockdown leads to a reduction of VGF, in neurons. VGF is also downregulated in the cortices from sporadic cases with major mental disease. A positive correlation of VGF single-nucleotide polymorphisms (SNPs) with social anhedonia was also observed. We now propose that VGF participates in a common pathophysiology of major mental disease.

A randomized clinical trial of histamine 2 receptor antagonism in treatment-resistant schizophrenia.

Histamine has important functions as regulator of several other key neurotransmitters. Patients with schizophrenia have lower histamine H1 receptor levels. Since a case report in 1990 of an effect of the H2 antagonist famotidine on negative symptoms in schizophrenia, some open-label trials have been performed, but no randomized controlled trial. Recently, it was shown that clozapine is a full inverse agonist at the H2 receptor. We performed a researcher-initiated, academically financed, double-blind, placebo-controlled, parallel-group, randomized trial with the histamine H2 antagonist famotidine in treatment-resistant schizophrenia. Thirty subjects with schizophrenia were randomized to have either famotidine (100 mg twice daily, n = 16) or placebo (n = 14) orally, added to their normal treatment regimen for 4 weeks. They were followed up weekly with the Scale for the Assessment of Negative Symptoms (SANS), the PANSS (Positive and Negative Syndrome Scale), and Clinical Global Impression (CGI) Scale. In the famotidine group, the SANS score was reduced by 5.3 (SD, 13.1) points, whereas in the placebo group the SANS score was virtually unchanged (mean change, +0.2 [SD, 9.5]). The difference did not reach statistical significance (P = 0.134) in Mann-Whitney U analysis. However, the PANSS Total score and the General subscore as well as the CGI showed significantly (P < 0.05) greater change in the famotidine group than in the placebo group. No significant adverse effects were observed. This is the first placebo-controlled, randomized clinical trial showing a beneficial effect of histamine H2 antagonism in schizophrenia. H2 receptor antagonism may provide a new alternative for the treatment of schizophrenia.

Predicting depression with psychopathology and temperament traits: the northern Finland 1966 birth cohort.

We studied the concurrent, predictive, and discriminate validity of psychopathology scales (e.g., schizotypal and depressive) and temperament traits for hospitalisations due to major depression. Temperament, perceptual aberration, physical and social anhedonia, Depression Subscale of Symptom Checklist (SCL-D), Hypomanic Personality Scale, Schizoidia Scale, and Bipolar II Scale were completed as part of the 31-year follow-up survey of the prospective Northern Finland 1966 Birth Cohort (n = 4941; 2214 males). Several of the scales were related to depression. Concurrent depression was especially related to higher perceptual aberration (effect size when compared to controls, d = 1.29), subsequent depression to high scores in SCL-D (d = 0.48). Physical anhedonia was lower in subjects with subsequent depression than those with other psychiatric disorders (d = -0.33, nonsignificant). Participants with concurrent (d = 0.70) and subsequent (d = 0.54) depression had high harm avoidance compared to controls, while differences compared to other psychiatric patients were small. Subjects with depression differed from healthy controls in most of the scales. Many of the scales were useful predictors for future hospital treatments, but were not diagnosis-specific. High harm avoidance is a potential indicator for subsequent depression.

Temperament clusters in a normal population: implications for health and disease.

BACKGROUND: The object of this study was to identify temperament patterns in the Finnish population, and to determine the relationship between these profiles and life habits, socioeconomic status, and health. METHODS/PRINCIPAL FINDINGS: A cluster analysis of the Temperament and Character Inventory subscales was performed on 3,761 individuals from the Northern Finland Birth Cohort 1966 and replicated on 2,097 individuals from the Cardiovascular Risk in Young Finns study. Clusters were formed using the k-means method and their relationship with 115 variables from the areas of life habits, socioeconomic status and health was examined. RESULTS: Four clusters were identified for both genders. Individuals from Cluster I are characterized by high persistence, low extravagance and disorderliness. They have healthy life habits, and lowest scores in most of the measures for psychiatric disorders. Cluster II individuals are characterized by low harm avoidance and high novelty seeking. They report the best physical capacity and highest level of income, but also high rate of divorce, smoking, and alcohol consumption. Individuals from Cluster III are not characterized by any extreme characteristic. Individuals from Cluster IV are characterized by high levels of harm avoidance, low levels of exploratory excitability and attachment, and score the lowest in most measures of health and well-being. CONCLUSIONS: This study shows that the temperament subscales do not distribute randomly but have an endogenous structure, and that these patterns have strong associations to health, life events, and well-being.

Proteomic, genomic and translational approaches identify CRMP1 for a role in schizophrenia and its underlying traits.

Schizophrenia is a chronic illness of heterogenous biological origin. We hypothesized that, similar to chronic progressive brain conditions, persistent functional disturbances of neurons would result in disturbed proteostasis in the brains of schizophrenia patients, leading to increased abundance of specific misfolded, insoluble proteins. Identification of such proteins would facilitate the elucidation of molecular processes underlying these devastating conditions. We therefore generated antibodies against pooled insoluble proteome of post-mortem brains from schizophrenia patients in order to identify unique, disease-specific epitopes. We successfully identified such an epitope to be present on collapsin-response mediator protein 1 (CRMP1) in biochemically purified, insoluble brain fractions. A genetic association analysis for the CRMP1 gene in a large Finnish population cohort (n = 4651) corroborated the association of physical and social anhedonia with the CRMP1 locus in a DISC1 (Disrupted-in-schizophrenia 1)-dependent manner. Physical and social anhedonia are heritable traits, present as chronic, negative symptoms of schizophrenia and severe major depression, thus constituting serious vulnerability factors for mental disease. Strikingly, lymphoblastoid cell lines derived from schizophrenia patients mirrored aberrant CRMP1 immunoreactivity by showing an increase of CRMP1 expression, suggesting its potential role as a blood-based diagnostic marker. CRMP1 is a novel candidate protein for schizophrenia traits at the intersection of the reelin and DISC1 pathways that directly and functionally interacts with DISC1. We demonstrate the impact of an interdisciplinary approach where the identification of a disease-associated epitope in post-mortem brains, powered by a genetic association study, is rapidly translated into a potential blood-based diagnostic marker.