Roselind Lieb

Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment

The stress hormone–regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression. To investigate a possible association between genes regulating the HPA axis and response to antidepressants and susceptibility for depression, we genotyped single-nucleotide polymorphisms in eight of these genes in depressed individuals and matched controls. We found significant associations of response to antidepressants and the recurrence of depressive episodes with single-nucleotide polymorphisms in FKBP5, a glucocorticoid receptor–regulating cochaperone of hsp-90, in two independent samples. These single-nucleotide polymorphisms were also associated with increased intracellular FKBP5 protein expression, which triggers adaptive changes in glucocorticoid receptor and, thereby, HPA-axis regulation. Individuals carrying the associated genotypes had less HPA-axis hyperactivity during the depressive episode. We propose that the FKBP5 variant–dependent alterations in HPA-axis regulation could be related to the faster response to antidepressant drug treatment and the increased recurrence of depressive episodes observed in this subgroup of depressed individuals. These findings support a central role of genes regulating the HPA axis in the causality of depression and the mechanism of action of antidepressant drugs.

Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people

Abstract Objective To investigate the relation between cannabis use and psychotic symptoms in individuals with above average predisposition for psychosis who first used cannabis during adolescence. Design Analysis of prospective data from a population based sample. Assessment of substance use, predisposition for psychosis, and psychotic symptoms was based on standardised personal interviews at baseline and at follow up four years later. Participants 2437 young people (aged 14 to 24 years) with and without predisposition for psychosis. Main outcome measure Psychotic symptoms at follow up as a function of cannabis use and predisposition for psychosis at baseline. Results After adjustment for age, sex, socioeconomic status, urbanicity, childhood trauma, predisposition for psychosis at baseline, and use of other drugs, tobacco, and alcohol, cannabis use at baseline increased the cumulative incidence of psychotic symptoms at follow up four years later (adjusted odds ratio 1.67, 95% confidence interval 1.13 to 2.46). The effect of cannabis use was much stronger in those with any predisposition for psychosis at baseline (23.8% adjusted difference in risk, 95% confidence interval 7.9 to 39.7, P = 0.003) than in those without (5.6%, 0.4 to 10.8, P = 0.033). The risk difference in the “predisposition” group was significantly greater than the risk difference in the “no predisposition” group (test for interaction 18.2%, 1.6 to 34.8, P = 0.032). There was a dose-response relation with increasing frequency of cannabis use. Predisposition for psychosis at baseline did not significantly predict cannabis use four years later (adjusted odds ratio 1.42, 95% confidence interval 0.88 to 2.31). Conclusion Cannabis use moderately increases the risk of psychotic symptoms in young people but has a much stronger effect in those with evidence of predisposition for psychosis.

Primary anxiety disorders and the development of subsequent alcohol use disorders : a 4-year community study of adolescents and young adults

BACKGROUND Cross-sectional findings in community surveys of adults suggest that adolescent anxiety disorders are strong predictors of the subsequent onset of alcohol use, abuse and dependence. However, prospective data that follow a sample of adolescents into adulthood are needed to confirm these associations. METHOD Baseline and 4-year follow-up data from the EDSP-Study, a prospective community survey of 3021 (2548 at follow-up) adolescents and young adults aged 14 to 24 years at baseline carried out in Munich, were used. DSM-IV anxiety disorders, alcohol use and alcohol use disorders were assessed with the Munich-Composite-International-Diagnostic-Interview (M-CIDI). Multiple logistic regression analysis, controlling for age, gender, other mental disorders, substance use disorders and antisocial behaviour was used to study the associations of baseline anxiety disorders with the subsequent onset and course of alcohol use and alcohol disorders. RESULTS Baseline social phobia significantly predicts the onsets of regular use and hazardous use and the persistence of dependence. Panic attacks significantly predict the onsets of hazardous use and abuse as well as the persistence of combined abuse/dependence. Panic disorder significantly predicts the persistence of combined abuse/dependence. Other anxiety disorders do not significantly predict any of the outcomes. CONCLUSIONS Panic and social phobia are predictors of subsequent alcohol problems among adolescents and young adults. Further studies are needed to investigate the underlying mechanisms and the potential value of targeted early treatment of primary panic and social phobia to prevent secondary alcohol use disorders.

Evidence That Onset of Clinical Psychosis Is an Outcome of Progressively More Persistent Subclinical Psychotic Experiences: An 8-Year Cohort Study

This study examined the hypothesis that developmental expression of psychometric risk in the form of subclinical psychotic experiences in the general population is usually transitory but in some instances may become abnormally persistent and progress to a clinical psychotic state. A prospective cohort study was conducted in a general population sample of 845 adolescents, aged 14-17 years, in Munich, Germany (Early Developmental Stages of Psychopathology Study). Expression of psychosis was assessed 4 times (T0-T3) over a period of 8.4 years. Transition from subclinical psychosis at T0-T2 to clinical psychosis in terms of impairment at T3 was examined as a function of the level of prior persistence of subclinical psychosis (present never, once, twice, or thrice). The more the subclinical psychosis persisted over the period T0-T2, the greater the risk of transition to clinical psychosis at T3 in a dose-response fashion (subclinical psychosis expression once over T0-T2: odds ratio [OR] = 1.5 [95% confidence interval {CI} = 0.6-3.7], posttest probability [PP] = 5%; twice: OR = 5.0 [95% CI = 1.6-15.9], PP = 16%; at all 3 measurements: OR = 9.9 [95% CI = 2.5-39.8], PP = 27%). Of all clinical psychosis at T3, more than a third (38.3%) was preceded by subclinical psychotic experiences at least once and a fifth (19.6%) at least twice. Consequently, a significant proportion of psychotic disorder may be conceptualized as the rare poor outcome of a common developmental phenotype characterized by persistence of psychometrically detectable subclinical psychotic experiences. This may be summarized descriptively as a psychosis proneness-persistence-impairment model of psychotic disorder.

Incidence and Risk Patterns of Anxiety and Depressive Disorders and Categorization of Generalized Anxiety Disorder

CONTEXT Controversy surrounds the diagnostic categorization of generalized anxiety disorder (GAD). OBJECTIVES To examine the incidence, comorbidity, and risk patterns for anxiety and depressive disorders and to test whether developmental features of GAD more strongly support a view of this condition as a depressive as opposed to an anxiety disorder. DESIGN Face-to-face, 10-year prospective longitudinal and family study with as many as 4 assessment waves. The DSM-IV Munich Composite International Diagnostic Interview was administered by clinically trained interviewers. SETTING Munich, Germany. PARTICIPANTS A community sample of 3021 individuals aged 14 to 24 years at baseline and 21 to 34 years at last follow-up. MAIN OUTCOME MEASURES Cumulative incidence of GAD, other anxiety disorders (specific phobias, social phobia, agoraphobia, and panic disorder), and depressive disorders (major depressive disorder, and dysthymia). RESULTS Longitudinal associations between GAD and depressive disorders are not stronger than those between GAD and anxiety disorders or between other anxiety and depressive disorders. Survival analyses reveal that the factors associated with GAD overlap more strongly with those specific to anxiety disorders than those specific to depressive disorders. In addition, GAD differs from anxiety and depressive disorders with regard to family climate and personality profiles. CONCLUSIONS Anxiety and depressive disorders appear to differ with regard to risk constellations and temporal longitudinal patterns, and GAD is a heterogeneous disorder that is, overall, more closely related to other anxiety disorders than to depressive disorders. More work is needed to elucidate the potentially unique aspects of pathways and mechanisms involved in the etiopathogenesis of GAD. Grouping GAD with depressive disorders, as suggested by cross-sectional features and diagnostic comorbidity patterns, minimizes the importance of longitudinal data on risk factors and symptom trajectories.

Transitions from first substance use to substance use disorders in adolescence: Is early onset associated with a rapid escalation?

BACKGROUND Early substance use (SU) in adolescence is known to be associated with an elevated risk of developing substance use disorders (SUD); it remains unclear though whether early SU is associated with more rapid transitions to SUD. OBJECTIVE To examine the risk and speed of transition from first SU (alcohol, nicotine, cannabis) to SUD as a function of age of first use. METHODS N=3021 community subjects aged 14-24 years at baseline were followed-up prospectively over 10-years. SU and SUD were assessed using the DSM-IV/M-CIDI. RESULTS (1) The conditional probability of substance-specific SU-SUD transition was the greatest for nicotine (36.0%) and the least for cannabis (18.3% for abuse, 6.2% for dependence) with alcohol in between (25.3% for abuse; 11.2% for dependence). (2) In addition to confirming early SU as a risk factor for SUD we find: (3) higher age of onset of any SU to be associated with faster transitions to SUD, except for cannabis dependence. (4) Transitions from first cannabis use (CU) to cannabis use disorders (CUD) occurred faster than for alcohol and nicotine. (5) Use of other substances co-occurred with risk and speed of transitions to specific SUDs. CONCLUSION Type of substance and concurrent use of other drugs are of importance for the association between age of first use and the speed of transitions to substance use disorders. Given that further research will identify moderators and mediators affecting these differential associations, these findings may have important implications for designing early and targeted interventions to prevent disorder progression.

Do subthreshold psychotic experiences predict clinical outcomes in unselected non-help-seeking population-based samples? A systematic review and meta-analysis, enriched with new results

BACKGROUND The base rate of transition from subthreshold psychotic experiences (the exposure) to clinical psychotic disorder (the outcome) in unselected, representative and non-help-seeking population-based samples is unknown. METHOD A systematic review and meta-analysis was conducted of representative, longitudinal population-based cohorts with baseline assessment of subthreshold psychotic experiences and follow-up assessment of psychotic and non-psychotic clinical outcomes. RESULTS Six cohorts were identified with a 3-24-year follow-up of baseline subthreshold self-reported psychotic experiences. The yearly risk of conversion to a clinical psychotic outcome in exposed individuals (0.56%) was 3.5 times higher than for individuals without psychotic experiences (0.16%) and there was meta-analytic evidence of dose-response with severity/persistence of psychotic experiences. Individual studies also suggest a role for motivational impairment and social dysfunction. The evidence for conversion to non-psychotic outcome was weaker, although findings were similar in direction. CONCLUSIONS Subthreshold self-reported psychotic experiences in epidemiological non-help-seeking samples index psychometric risk for psychotic disorder, with strong modifier effects of severity/persistence. These data can serve as the population reference for selected and variable samples of help-seeking individuals at ultra-high risk, for whom much higher transition rates have been indicated.

Evidence That Psychotic Symptoms Are Prevalent in Disorders of Anxiety and Depression, Impacting on Illness Onset, Risk, and Severity—Implications for Diagnosis and Ultra–High Risk Research

BACKGROUND It is commonly assumed that there are clear lines of demarcation between anxiety and depressive disorders on the one hand and psychosis on the other. Recent evidence, however, suggests that this principle may be in need of updating. METHODS Depressive and/or anxiety disorders, with no previous history of psychotic disorder, were examined for the presence of psychotic symptoms in a representative community sample of adolescents and young adults (Early Developmental Stages of Psychopathology study; n = 3021). Associations and consequences of psychotic symptomatology in the course of these disorders were examined in terms of demographic distribution, illness severity, onset of service use, and risk factors. RESULTS Around 27% of those with disorders of anxiety and depression displayed one or more psychotic symptoms, vs 14% in those without these disorders (OR 2.23, 95% CI 1.89-2.66, P < .001). Presence as compared with nonpresence of psychotic symptomatology was associated with younger age (P < .0001), male sex (P < .0058), and poorer illness course (P < .0002). In addition, there was greater persistence of schizotypal (P < .0001) and negative symptoms (P < .0170), more observable illness behavior (P < .0001), greater likelihood of service use (P < .0069), as well as more evidence of familial liability for mental illness (P < .0100), exposure to trauma (P < .0150), recent and more distant life events (P < .0006-.0244), cannabis use (P < .0009), and any drug use (P < .0008). CONCLUSION Copresence of psychotic symptomatology in disorders of anxiety and depression is common and a functionally and etiologically highly relevant feature, reinforcing the view that psychopathology is represented by a network or overlapping and reciprocally impacting dimensional liabilities.

Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study

Objective To determine whether use of cannabis in adolescence increases the risk for psychotic outcomes by affecting the incidence and persistence of subclinical expression of psychosis in the general population (that is, expression of psychosis below the level required for a clinical diagnosis). Design Analysis of data from a prospective population based cohort study in Germany (early developmental stages of psychopathology study). Setting Population based cohort study in Germany. Participants 1923 individuals from the general population, aged 14-24 at baseline. Main outcome measure Incidence and persistence of subthreshold psychotic symptoms after use of cannabis in adolescence. Cannabis use and psychotic symptoms were assessed at three time points (baseline, T2 (3.5 years), T3 (8.4 years)) over a 10 year follow-up period with the Munich version of the composite international diagnostic interview (M-CIDI). Results In individuals who had no reported lifetime psychotic symptoms and no reported lifetime cannabis use at baseline, incident cannabis use over the period from baseline to T2 increased the risk of later incident psychotic symptoms over the period from T2 to T3 (adjusted odds ratio 1.9, 95% confidence interval 1.1 to 3.1; P=0.021). Furthermore, continued use of cannabis increased the risk of persistent psychotic symptoms over the period from T2 to T3 (2.2, 1.2 to 4.2; P=0.016). The incidence rate of psychotic symptoms over the period from baseline to T2 was 31% (152) in exposed individuals versus 20% (284) in non-exposed individuals; over the period from T2 to T3 these rates were 14% (108) and 8% (49), respectively. Conclusion Cannabis use is a risk factor for the development of incident psychotic symptoms. Continued cannabis use might increase the risk for psychotic disorder by impacting on the persistence of symptoms.

Does normal developmental expression of psychosis combine with environmental risk to cause persistence of psychosis ? A psychosis proneness-persistence model

BACKGROUND Research suggests that low-grade psychotic experiences in the general population are a common but transitory developmental phenomenon. Using two independent general population samples, the hypothesis was examined that common, non-clinical developmental expression of psychosis may become abnormally persistent when synergistically combined with developmental exposures that may impact on behavioural and neurotransmitter sensitization such as cannabis, trauma and urbanicity. METHOD The amount of synergism was estimated from the additive statistical interaction between baseline cannabis use, childhood trauma and urbanicity on the one hand, and baseline psychotic experiences on the other, in predicting 3-year follow-up psychotic experiences, using data from two large, longitudinal, random population samples from the Netherlands [The Netherlands Mental Health Survey and Incidence Study (NEMESIS)] and Germany [The Early Developmental Stages of Psychopathology (EDSP) study]. RESULTS The 3-year persistence rates of psychotic experiences were low at 26% in NEMESIS and 31% in EDSP. However, persistence rates were progressively higher with greater baseline number of environmental exposures in predicting follow-up psychotic experiences (chi2=6.9, df=1, p=0.009 in NEMESIS and chi2=4.2, df=1, p=0.04 in EDSP). Between 21% and 83% (NEMESIS) and 29% and 51% (EDSP) of the subjects exposed to both environmental exposures and psychotic experiences at baseline had persistence of psychotic experiences at follow-up because of the synergistic action of the two factors. CONCLUSION The findings suggest that environmental risks for psychosis act additively, and that the level of environmental risk combines synergistically with non-clinical developmental expression of psychosis to cause abnormal persistence and, eventually, need for care.