Alessandro Colasanti

Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin

Psychedelic drugs have a long history of use in healing ceremonies, but despite renewed interest in their therapeutic potential, we continue to know very little about how they work in the brain. Here we used psilocybin, a classic psychedelic found in magic mushrooms, and a task-free functional MRI (fMRI) protocol designed to capture the transition from normal waking consciousness to the psychedelic state. Arterial spin labeling perfusion and blood-oxygen level-dependent (BOLD) fMRI were used to map cerebral blood flow and changes in venous oxygenation before and after intravenous infusions of placebo and psilocybin. Fifteen healthy volunteers were scanned with arterial spin labeling and a separate 15 with BOLD. As predicted, profound changes in consciousness were observed after psilocybin, but surprisingly, only decreases in cerebral blood flow and BOLD signal were seen, and these were maximal in hub regions, such as the thalamus and anterior and posterior cingulate cortex (ACC and PCC). Decreased activity in the ACC/medial prefrontal cortex (mPFC) was a consistent finding and the magnitude of this decrease predicted the intensity of the subjective effects. Based on these results, a seed-based pharmaco-physiological interaction/functional connectivity analysis was performed using a medial prefrontal seed. Psilocybin caused a significant decrease in the positive coupling between the mPFC and PCC. These results strongly imply that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brains key connector hubs, enabling a state of unconstrained cognition.

Clinical pharmacokinetics of atypical antipsychotics : A critical review of the relationship between plasma concentrations and clinical response

In the past, the information about the dose-clinical effectiveness of typical antipsychotics was not complete and this led to the risk of extrapyramidal adverse effects. This, together with the intention of improving patients’ quality of life and therapeutic compliance, resulted in the development of atypical or second-generation antipsychotics (SGAs). This review will concentrate on the pharmacokinetics and metabolism of Clozapine, risperidone, olanzapine, quetiapine, amisulpride, ziprasidone, aripiprazole and sertindole, and will discuss the main aspects of their pharmacodynamics.In psychopharmacology, therapeutic drug monitoring studies have generally concentrated on controlling compliance and avoiding adverse effects by keeping long-term exposure to the minimal effective blood concentration. The rationale for using therapeutic drug monitoring in relation to SGAs is still a matter of debate, but there is growing evidence that it can improve efficacy, especially when patients do not respond to therapeutic doses or when they develop adverse effects.Here, we review the literature concerning the relationships between plasma concentrations of SGAs and clinical responses by dividing the studies on the basis of the length of their observation periods.Studies with clozapine evidenced a positive relationship between plasma concentrations and clinical response, with a threshold of 350–420 ng/mL associated with good clinical response. The usefulness of therapeutic drug monitoring is well established because high plasma concentrations of clozapine can increase the risk of epileptic seizures. Plasma clozapine concentrations seem to be influenced by many factors such as altered cytochrome P450 1A4 activity, age, sex and smoking.The pharmacological effects of risperidone depend on the sum of the plasma concentrations of risperidone and its 9-hydroxyrisperidone metabolite, so monitoring the plasma concentrations of the parent compound alone can lead to erroneous interpretations. Despite a large variability in plasma drug concentrations, the lack of studies using fixed dosages, and discrepancies in the results, it seems that monitoring the plasma concentrations of the active moiety may be useful. However, no therapeutic plasma concentration range for risperidone has yet been clearly established. A plasma threshold concentration for parkinsonian side effects has been found to be 74 ng/mL. Moreover, therapeutic drug monitoring may be particularly useful in the switch between the oral and the long-acting injectable form.The reviewed studies on olanzapine strongly indicate a relationship between clinical outcomes and plasma concentrations. Olanzapine therapeutic drug monitoring can be considered very useful in assessing therapeutic efficacy and controlling adverse events. A therapeutic range of 20–50 ng/mL has been found.There is little evidence in favour of the existence of a relationship between plasma quetiapine concentrations and clinical responses, and an optimal therapeutic range has not been identified. Positron emission tomography studies of receptor blockade indicated a discrepancy between the time course of receptor occupancy and plasma quetiapine concentrations. The value of quetiapine plasma concentration monitoring in clinical practice is still controversial.Preliminary data suggested that a therapeutic plasma amisulpride concentration of 367 ng/mL was associated with clinical improvement. A therapeutic range of 100–400 ng/mL is proposed from non-systematic clinical experience.There is no direct evidence concerning optimal plasma concentration ranges of ziprasidone, aripiprazole or sertindole.

Within-Subject Comparison of [11C]-( + )-PHNO and [11C]raclopride Sensitivity to Acute Amphetamine Challenge in Healthy Humans

[11C]PHNO is a D2/D3 agonist positron emission tomography radiotracer, with higher in vivo affinity for D3 than for D2 receptors. As [11C]-( + )-PHNO is an agonist, its in vivo binding is expected to be more affected by acute fluctuations in synaptic dopamine than that of antagonist radiotracers such as [11C]raclopride. In this study, the authors compared the effects of an oral dose of the dopamine releaser amphetamine (0.3 mg/kg) on in vivo binding of [11C]-( + )-PHNO and [11C]raclopride in healthy subjects, using a within-subjects, counterbalanced, open-label design. In the dorsal striatum, where the density of D3 receptors is negligible and both tracers predominantly bind to D2 receptors, the reduction of [11C]-( + )-PHNO binding potential (BPND) was 1.5 times larger than that of [11C]raclopride. The gain in sensitivity associated with the agonist [11C]-( + )-PHNO implies that ~65% of D2 receptors are in the high-affinity state in vivo. In extrastriatal regions, where [11C]-( + )-PHNO predominantly binds to D3 receptors, the amphetamine effect on [11C]-( + )-PHNO BPND was even larger, consistent with the higher affinity of dopamine for D3. This study indicates that [11C]- ( + )-PHNO is superior to [11C]raclopride for studying acute fluctuations in synaptic dopamine in the human striatum. [11C]-( + )-PHNO also enables measurement of synaptic dopamine in D3 regions.

Determination of [11C]PBR28 binding potential in vivo: a first human TSPO blocking study

Positron emission tomography (PET) targeting the 18 kDa translocator protein (TSPO) is used to quantify neuroinflammation. Translocator protein is expressed throughout the brain, and therefore a classical reference region approach cannot be used to estimate binding potential (BP ND ). Here, we used blockade of the TSPO radioligand [11C]PBR28 with the TSPO ligand XBD173, to determine the non-displaceable volume of distribution (V ND ), and hence estimate the BP ND . A total of 26 healthy volunteers, 16 high-affinity binders (HABs) and 10 mixed affinity binders (MABs) underwent a [11C]PBR28 PET scan with arterial sampling. Six of the HABs received oral XBD173 (10 to 90 mg), 2 hours before a repeat scan. In XBD173-dosed subjects, V ND was estimated via the occupancy plot. Values of BP ND for all subjects were calculated using this V ND estimate. Total volume of distribution (V T ) of MABs (2.94 ± 0.31) was lower than V T of HABs (4.33 ± 0.29) (P<0.005). There was dose-dependent occupancy of TSPO by XBD173 (ED50 = 0.34 ± 0.13 mg/kg). The occupancy plot provided a V ND estimate of 1.98 (1.69, 2.26). Based on these V ND estimates, BP ND for HABs is approximately twice that of MABs, consistent with predictions from in vitro data. Our estimates of [11C]PBR28 V ND and hence BP ND in the healthy human brain are consistent with in vitro predictions. XBD173 blockade provides a practical means of estimating V ND for TSPO targeting radioligands.

Opioids and anxiety

The opioid system plays a crucial role in the neural modulation of anxiety. The involvement of opioid ligands and receptors in physiological and dysfunctional forms of anxiety is supported by findings from a wide range of preclinical and clinical studies, including clinical trials, experimental research, and neuroimaging, genetic, and epidemiological data. In this review we provide a summary of studies from a variety of research disciplines to elucidate the role of the opioid system in the neurobiology of anxiety. First, we report data from preclinical studies using animal models to examine the modulatory role of central opioid system on defensive responses conducive to fear and anxiety. Second, we summarize the human literature providing evidence that clinical and experimental human studies are consistent with preclinical models. The implication of these data is that activation of the opioid system leads to anxiolytic responses both in healthy subjects and in patients suffering from anxiety disorders. The role of opioids in suppressing anxiety may serve as an adaptive mechanism, collocated in the general framework of opioid neurotransmission blunting acute negative and distressing affective responses.

Quantification of the Specific Translocator Protein Signal of 18F-PBR111 in Healthy Humans: A Genetic Polymorphism Effect on In Vivo Binding

PET is used to image active inflammatory processes by targeting the translocator protein (TSPO). In vitro, second-generation TSPO radioligands, such as PBR111, have been shown to bind to human tissue samples with either high affinity (high-affinity binders, HABs), low affinity (low-affinity binders, LABs), or an intermediate, mixed affinity (mixed-affinity binders, MABs). We previously explained these differences in affinity in human tissue via the rs6971 polymorphism in the TSPO gene and predicted that the specific signal from PET ligands in vivo would vary accordingly. In silico modeling predicted that 18F-PBR111 would have a moderate to high specific-to-nonspecific ratio in the normal human brain. To test these predictions, we present here the analysis and modeling of 18F-PBR111 data in healthy humans. Methods: Twenty-one subjects (9 HABs, 8 MABs, and 4 LABs), 28–62 y old, genotyped for the rs6971 polymorphism, underwent 120-min PET scans with arterial sampling after a bolus injection of 18F-PBR111. Compartmental models and Logan graphical methods enabled estimation of the total volume of distribution (VT) in regions of interest (ROIs). To evaluate the specific signal, we developed 2 methods to estimate the nondisplaceable volume of distribution (VND): the first assumed that the in vitro affinity ratio of 18F-PBR111 in HABs relative to LABs (4-fold) is preserved in vivo; the second modeled the difference in the HAB and MAB signals in the context of an occupancy plot. Results: A 2-tissue-compartment model described the data well, and a significant difference was found between the VT of HABs, MABs, and LABs across all ROIs examined (P < 0.05). We also found a significant correlation between VT and age for both HABs and MABs in most ROIs. The average VND estimated by the 2 methods was 1.18 ± 0.35 (method I: VND = 0.93, method II: VND = 1.42), implying that the 18F-PBR111 BPND was 2.78 ± 0.46 in HABs, 1.48 ± 0.28 in MABs, and 0.51 ± 0.17 in LABs and that the in vivo affinity ratio was similar to that measured in vitro. Conclusion: 18F-PBR111 shows a high specific signal in the healthy human brain in vivo. A large component of the variability in the signal across subjects is explained by genetic variation and age, indicating that 18F-PBR111 can be used for the quantitative assessment of TSPO expression.

In Vivo Assessment of Brain White Matter Inflammation in Multiple Sclerosis with 18 F-PBR111 PET

PET radioligand binding to the 18-kD translocator protein (TSPO) in the brains of patients with multiple sclerosis (MS) primarily reflects activated microglia and macrophages. We previously developed genetic stratification for accurate quantitative estimation of TSPO using second-generation PET radioligands. In this study, we used 18F-PBR111 PET and MR imaging to measure relative binding in the lesional, perilesional, and surrounding normal-appearing white matter of MS patients, as an index of the innate immune response. Methods: 18F-PBR111 binding was quantified in 11 MS patients and 11 age-matched healthy volunteers, stratified according to the rs6971 TSPO gene polymorphism. Fluid-attenuated inversion recovery and magnetization transfer ratio (MTR) MR imaging were used to segment the white matter in MS patients as lesions, perilesional volumes, nonlesional white matter with reduced MTR, and nonlesional white matter with normal MTR. Results: 18F-PBR111 binding was higher in the white matter lesions and perilesional volumes of MS patients than in white matter of healthy controls (P < 0.05). Although there was substantial heterogeneity in binding between different lesions, a within-subject analysis showed higher 18F-PBR111 binding in MS lesions (P < 0.05) and in perilesional (P < 0.05) and nonlesional white matter with reduced MTR (P < 0.005) than in nonlesional white matter with a normal MTR. A positive correlation was observed between the mean 18F-PBR111 volume of distribution increase in lesions relative to nonlesional white matter with a normal MTR and the MS severity score (Spearman ρ = 0.62, P < 0.05). Conclusion: This study demonstrates that quantitative TSPO PET with a second-generation radioligand can be used to characterize innate immune responses in MS in vivo and provides further evidence supporting an association between the white matter TSPO PET signal in lesions and disease severity. Our approach is practical for extension to studies of the role of the innate immune response in MS for differentiation of antiinflammatory effects of new medicines and their longer term impact on clinical outcome.

Determination of |[lsqb]|11C|[rsqb]|PBR28 binding potential in vivo: a first human TSPO blocking study

Positron emission tomography (PET) targeting the 18 kDa translocator protein (TSPO) is used to quantify neuroinflammation. Translocator protein is expressed throughout the brain, and therefore a classical reference region approach cannot be used to estimate binding potential (BP ND ). Here, we used blockade of the TSPO radioligand [11C]PBR28 with the TSPO ligand XBD173, to determine the non-displaceable volume of distribution (V ND ), and hence estimate the BP ND . A total of 26 healthy volunteers, 16 high-affinity binders (HABs) and 10 mixed affinity binders (MABs) underwent a [11C]PBR28 PET scan with arterial sampling. Six of the HABs received oral XBD173 (10 to 90 mg), 2 hours before a repeat scan. In XBD173-dosed subjects, V ND was estimated via the occupancy plot. Values of BP ND for all subjects were calculated using this V ND estimate. Total volume of distribution (V T ) of MABs (2.94 ± 0.31) was lower than V T of HABs (4.33 ± 0.29) (P<0.005). There was dose-dependent occupancy of TSPO by XBD173 (ED50 = 0.34 ± 0.13 mg/kg). The occupancy plot provided a V ND estimate of 1.98 (1.69, 2.26). Based on these V ND estimates, BP ND for HABs is approximately twice that of MABs, consistent with predictions from in vitro data. Our estimates of [11C]PBR28 V ND and hence BP ND in the healthy human brain are consistent with in vitro predictions. XBD173 blockade provides a practical means of estimating V ND for TSPO targeting radioligands.

Carbon dioxide-induced emotion and respiratory symptoms in healthy volunteers

A number of evidences have established that panic and respiration are closely related. Clinical studies indicated that respiratory sensations constitute a discrete cluster of panic symptoms and play a major role in the pathophysiology of panic. The aim of the present study was to explore the phenomenology of an experimental model of panic in healthy volunteers based on the hypothesis that: (1) we can isolate discrete clusters of panic symptoms, (2) respiratory symptoms represent a distinct cluster of panic symptoms, and (3) respiratory symptoms are the best predictor of the subjective feeling of panic, as defined in the DSM IV criteria.Sixty-four healthy volunteers received a double inhalation of four mixtures containing 0, 9, 17.5 and 35% CO2, respectively, in a double-blind, cross-over, random design. An electronic visual analog scale and the Panic Symptom List (PSL) were used to assess subjective ‘fear/discomfort’ and panic symptoms, respectively. Statistical analyses consisted of Spearmans correlations, a principal component factor analysis of the 13 PSL symptoms, and linear regressions analyses.The factor analysis extracted three clusters of panic symptoms: respiratory, cognitive, and neurovegetative (r2=0.65). Respiratory symptoms were highly related to subjective feeling of fear/discomfort specifically in the CO2-enriched condition. Moreover, the respiratory component was the most important predictor of the subjective feeling of ‘fear/discomfort’ (β=0.54).The discrete clusters of symptoms observed in this study were similar to those elicited in panic attacks naturally occurring in patients affected by panic disorder. Consistent with the idea that respiration plays a crucial role in the pathophysiology of panic, we found that respiratory symptoms were the best predictors the subjective state defined in the DSM IV criteria for panic.

Acids in the brain: a factor in panic?

Several methods to experimentally induce panic cause profound acid-base disturbances. Evidence suggests that CO2 inhalations, lactate infusions and, to a certain extent, voluntary hyperventilation can conceivably lead to a common scenario of brain acidosis in the face of disparate intravascular pH alterations. The importance of this event is reflected in data that support a model in which experimental panic attacks, as proxy to those occurring spontaneously, constitute a response to acute brain acidosis. Given that central CO2/H+ chemoreception is an important drive for ventilation, and many chemosensitive neurons are related to respiration and arousal, this model can explain much of the connection between panic and respiration. We propose that the shared characteristics of CO2/H+ sensing neurons overlap to a point where threatening disturbances in brain pH homeostasis, such as those produced by CO2 inhalations, elicit a primal emotion that can range from breathlessness to panic.