Johan Lataster

Delta-9-tetrahydrocannabinol-induced dopamine release as a function of psychosis risk: 18F-fallypride positron emission tomography study.

Cannabis use is associated with psychosis, particularly in those with expression of, or vulnerability for, psychotic illness. The biological underpinnings of these differential associations, however, remain largely unknown. We used Positron Emission Tomography and 18F-fallypride to test the hypothesis that genetic risk for psychosis is expressed by differential induction of dopamine release by Δ9-THC (delta-9-tetrahydrocannabinol, the main psychoactive ingredient of cannabis). In a single dynamic PET scanning session, striatal dopamine release after pulmonary administration of Δ9-THC was measured in 9 healthy cannabis users (average risk psychotic disorder), 8 patients with psychotic disorder (high risk psychotic disorder) and 7 un-related first-degree relatives (intermediate risk psychotic disorder). PET data were analyzed applying the linear extension of the simplified reference region model (LSRRM), which accounts for time-dependent changes in 18F-fallypride displacement. Voxel-based statistical maps, representing specific D2/3 binding changes, were computed to localize areas with increased ligand displacement after Δ9-THC administration, reflecting dopamine release. While Δ9-THC was not associated with dopamine release in the control group, significant ligand displacement induced by Δ9-THC in striatal subregions, indicative of dopamine release, was detected in both patients and relatives. This was most pronounced in caudate nucleus. This is the first study to demonstrate differential sensitivity to Δ9-THC in terms of increased endogenous dopamine release in individuals at risk for psychosis.

COMT Val158Met genotype selectively alters prefrontal [18F]fallypride displacement and subjective feelings of stress in response to a psychosocial stress challenge.

Catechol-O-methyltransferase (COMT) plays an essential role in degradation of extracellular dopamine in prefrontal regions of the brain. Although a polymorphism in this gene, COMT Val158Met, affects human behavior in response to stress little is known about its effect on dopaminergic activity associated with the human stress response, which may be of interest for stress-related psychiatric disorders such as psychosis. We aimed to investigate the effect of variations in COMT genotype on in vivo measures of stress-induced prefrontal cortex (PFC) dopaminergic processing and subjective stress responses. A combined sample of healthy controls and healthy first-degree relatives of psychosis patients (n = 26) were subjected to an [18F]fallypride Positron Emission Tomography scan. Psychosocial stress during the scan was induced using the Montreal Imaging Stress Task and subjective stress was assessed every 12 minutes. Parametric t-maps, generated using the linear extension of the simplified reference region model, revealed an effect of COMT genotype on the spatial extent of [18F]fallypride displacement. Detected effects of exposure to psychosocial stress were unilateral and remained restricted to the left superior and right inferior frontal gyrus, with Met-hetero- and homozygotes showing less [18F]fallypride displacement than Val-homozygotes. Additionally, Met-hetero- and homozygotes experienced larger subjective stress responses than Val-homozygotes. The direction of the effects remained the same when the data was analyzed separately for controls and first-degree relatives. The human stress response may be mediated in part by COMT-dependent dopaminergic PFC activity, providing speculation for the neurobiology underlying COMT-dependent differences in human behaviour following stress. Implications of these results for stress-related psychopathology and models of dopaminergic functioning are discussed.

Familial Liability to Psychosis Is Associated With Attenuated Dopamine Stress Signaling in Ventromedial Prefrontal Cortex

OBJECTIVE Patients diagnosed with a psychotic disorder and their first-degree relatives display increased reactivity to stress. Theory predicts that experience of psychosocial stress is associated both with ventromedial prefrontal and mesolimbic dopamine neurotransmission. However, while there is evidence of aberrant striatal dopamine processing in psychotic disorder, the role of the prefrontal cortex remains under-researched. This study aimed at investigating stress-induced in vivo dopamine release in ventromedial prefrontal cortex (vmPFC) of individuals at familial risk for psychosis. METHOD Fourteen healthy first-degree relatives of patients with a diagnosis of psychotic disorder and 10 control subjects underwent a single dynamic positron emission tomography (PET) scanning session after intravenous administration of 183.2 (SD = 7.6) MBq [(18)F]fallypride. Psychosocial stress was initiated at 100 min postinjection using a computerized mental arithmetic task with social evaluative threat components. PET data were analyzed using the linearized simplified reference region model. Regression analyses were performed to compare the spatial extent of task-related ligand displacement between control subjects and relatives and to find how it related to self-rated experiences of psychosocial stress and psychosis. RESULTS First-degree relatives displayed hyporeactive dopamine signaling in the vmPFC in response to stress. Increased levels of subjectively rated stress were associated with increased intensity of psychotic experiences. This effect was particularly pronounced in first-degree relatives. CONCLUSION Although previous studies have hypothesized a role for prefrontal dopamine dysfunction in psychosis, this study, to our knowledge, is the first in vivo human imaging study showing attenuated (ie, hyporeactive) dopamine stress neuromodulation in vmPFC of individuals at familial risk for psychosis.

Psychotic Reactivity to Daily Life Stress and the Dopamine System: A Study Combining Experience Sampling and [F-18] fallypride Positron Emission Tomography

Stressful life events increase the risk for psychosis, and the subjective experience of stress related to daily life activities drives moment-to-moment variation in psychotic intensity. Positron emission tomography (PET) studies suggest that dopaminergic (DAergic) activity mediates the behavioral response to an experimental stressor. However, it is not known how alterations in this DAergic stress response relate to the subjective experience of stress in real life situations assessed in momentary assessment studies. This study combined [18F]fallypride PET with an Experience Sampling ambulatory assessment approach to examine the association between the prefrontal DAergic response to experimentally induced stress and real life psychotic reactivity to the subjective experience of stress in daily life. Healthy first-degree relatives of individuals with a psychotic disorder (N = 14) and healthy controls (N = 11) participated in (a) a psychosocial [18F]fallypride PET stress paradigm and (b) an experience sampling study, using a structured diary approach. Mixed multilevel random intercept models revealed that stress-induced [18F]fallypride displacement, indicative of DAergic activity, in ventromedial prefrontal cortex (VMPFC) was associated with psychotic reactivity to daily life stress in the entire sample. Lower levels of [18F]fallypride displacement to stress predicted increased psychotic reactivity to daily life stress. This study combined PET neuroimaging with real life behavioral assessments in the investigation of psychotic symptoms; we showed decreased [18F]fallypride displacement to stress in VMPFC to be associated with increased psychotic reactivity to daily life stress. The preliminary evidence in this study demonstrates that it is possible to acquire a grasp on how brain function is associated with contextualized experience, which has relevance for neuroimaging studies in general.

Resilience to affective disorders: A comparative validation of two resilience scales

BACKGROUND Resilience to affective disorders in rehabilitating patients or in individuals with a severe disability is of special research interest. However, there is no gold standard for measuring resilience. We aimed to test the accuracy of the Dutch translation of the Brief Resilience Scale (BRSnl) and of the Resilience Scale (RSnl) in recognizing rehabilitating patients without anxiety and depression, and to determine the reliability and construct validity of both scales. METHODS A within-subjects longitudinal study with six assessments, each one week apart. Forty residents of a nursing home rehabilitating unit were interviewed to assess resilience (BRSnl and RSnl), optimism and pessimism (LOT-R), depression and anxiety (HADS), positive and negative affect (PANAS), and pain (VAS). RESULTS Receiver operating characteristic analyses for recognizing the absence of depression and anxiety (HADS-score≤7) revealed better accuracy (P=0.038) for the BRSnl (AUC=0.84; p<0.0001) than for the RSnl (AUC=0.68; P=0.017). The scales correlated moderately at baseline (rs=0.35; p=0.026), and at four-week follow-up (rs=0.50; p=0.004). The RSnl was positively associated with positive outcomes (optimism and positive affect), and the BRSnl positively with positive outcomes, and negatively with negative outcomes (pessimism, anxiety and negative affect). The RSnl showed a better four-week test-retest reliability (ICC, 0.94; 95% CI, 0.87 to 0.97) than the BRSnl (0.66; 95% CI, 0.29 to.83). LIMITATIONS Short study duration, a relatively small sample. CONCLUSION The BRSnl showed better performance in detecting people without depression and anxiety than the RSnl, and performed better on construct validity.

Psychotic exacerbation and emotional dampening in the daily life of patients with schizophrenia switched to aripiprazole therapy: a collection of standardized case reports

Background: Blockade of the dopamine D2 receptor is a key mechanism in the antipsychotic treatment of patients with a psychotic disorder, but may also induce emotional deficits. The partial D2 agonistic profile of aripiprazole has, therefore, been suggested to favor emotional wellbeing compared with the pure dopamine antagonistic properties of traditional antipsychotics. Method: The current study used the experience sampling method (a structured diary technique) to assess the effects of switching from treatment with traditional dopamine antagonist antipsychotics to treatment with the partial dopamine agonist aripiprazole on emotional wellbeing in the daily life of 13 patients with a diagnosis of schizophrenia. Results: More than half of all patients experienced exacerbation of psychotic symptoms after they had switched to the aripiprazole medication regime, consequently resulting in dropout of the study. Furthermore, switching to aripiprazole treatment, when effective in terms of symptom reduction, was accompanied by decreased feelings of both positive and negative affect in daily life, suggestive of a general state of emotional dampening. Conclusions: Although the scale of the current study and the 54% dropout rate call for careful interpretation of the data, implementation of ecological monitoring in psychopharmacological research may open up new avenues for untangling the working mechanisms of compounds with regard to their impact on mental states.

Reciprocal relationships between State gratitude and high- and low-arousal positive affects in daily life: A time-lagged ecological assessment study

ABSTRACT This study assessed whether state gratitude and high and low-arousal positive affect show reciprocal relationships in daily life, and whether these relationships are dependent of inter-individual differences in positive mental health or psychopathology. 106 participants reported on momentary gratitude and positive affects throughout 7 consecutive days, using the Experience Sampling Method. Multilevel time-lagged regression analyses showed that state gratitude, cheerfulness and satisfaction reciprocally predict one another from one moment to the next. The strength of the prospective relationships between state gratitude(t-1) and both cheerfulness(t) and satisfaction(t) did not vary as a function of inter-individual differences in positive mental health or psychopathology. However, the prospective effects of both cheerfulness(t-1) and satisfaction(t-1) on state gratitude(t) were significantly stronger for individuals with low vs. high levels of psychopathology. In addition, the prospective effect of cheerfulness(t-1) on state gratitude(t) was significantly stronger for those with high vs. low positive mental health.

Overall cortisol, diurnal slope, and stress reactivity in psychosis: An experience sampling approach

OBJECTIVE Results from experimental studies suggest that psychosis and psychosis liability are associated with increased cortisol levels and blunted cortisol reactivity, and that use of antipsychotics may reduce these aberrations. Here, we report on overall cortisol, diurnal slope, and cortisol stress reactivity in everyday life in psychosis and psychosis liability using the experience sampling method (ESM). METHODS Our sample consisted of individuals diagnosed with psychotic disorder currently on (MPD; n = 53) or off antipsychotic medication (NMPD; n = 20), first-degree relatives of psychotic patients (REL; n = 47), and healthy volunteers (HV; n = 67). Saliva samples were collected throughout the day on six consecutive days and analyzed for cortisol levels. Simultaneously, stressfulness of the current activity was assessed with ESM questionnaires. RESULTS We found no group differences in overall cortisol level between groups, but REL had a steeper diurnal slope than HV; in MPD a trend was found in the same direction. Regarding reactivity to stressful activities, results indicated attenuation of the cortisol response in both patient groups compared to HV. CONCLUSION These results do not confirm reports of increased cortisol levels in psychosis, but provide evidence of stress-related cortisol alterations in everyday life.