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The article presents a study of literature on the clinical effects, pharmacokinetics and pharmacodynamics of antipsychotics in older people and potential mechanisms underlying the age-related antipsychotic sensitivity. It attributes increased sensitivity to antipsychotics to peripheral pharmacokinetic changes associated with the aging process. The limitations in the study are explained. Lower antipsychotic doses are said to be needed in light of age-related functional decline in the dopaminergic system.

Objective: The primary objective of this review article is to provide a coherent, systematic synthesis of the literature on the management of suicidality in schizophrenia that is relevant to the front-line clinician. Method: Literature searches were conducted on MEDLINE (1996 to 2007) and PubMed (1993 to 2007), using the key words ‘schizophrenia’ and ‘suicide,’ as well as references from the resulting articles. I used my own clinical experience to create fictional case examples to illustrate the applicability of the literature discussed in this paper. Results: Suicidality in schizophrenia is high, and early detection relies on the appreciation and evaluation of the clinical manifestations of depression, despair, and hopelessness, as well as on the nature and severity of the psychotic experience itself, particularly in recent-onset patients with higher cognitive function and educational background. Clinical management includes ensuring immediate safety, the use of psychosocial techniques to address depression and psychosocial stressors, targeted pharmacotherapy for depression and psychosis, and adequate discharge planning. Clozapine is the only antipsychotic with good evidence for efficacy in decreasing suicidal behaviour in schizophrenia. Conclusions: The optimal management of suicidality in schizophrenia involves the incorporation of traditional bedside clinical skills, selection of psychosocial modalities based on individual needs, and selective pharmacotherapy directed primarily at psychotic and depressive symptoms. [ABSTRACT FROM AUTHOR]

Objectives: Anti psychotic medications improve psychosis but often induce a state of dysphoria in patients. Blockade of the dopamine D2 receptors, which is thought to mediate their efficacy, has also been im- plicated in producing this adverse subjective experience. The authors present the first double-blind controlled study to examine the relationship between striatal and extrastriatal dopamine D2 receptor binding potential and occupancy values and adverse subjective experience. Method: Patients with recent-onset psychosis (N=12) were randomly assigned to low or high doses of olanzapine or risperidone. Subjective experiences, motor side effects, and striatal and extrastriatal dopamine D2 receptors (determined with ([11C]raclopride and [11C]FLB 457 PET scans, respectively) were evaluated after 2 weeks of continuous antipsychotic treatment. Results: Higher dopamine D2 receptor occupancy and binding potentials in the striatal (dorsal and ventral), temporal, and insular regions were associated with subjective experience. The finding was confirmed with two convergent methods of analysis (region-of-interest and voxel-based statistics), and the same relation- ship was observed using two different dopamine receptor measures (observed binding potential values and age- and sex-corrected occupancy values). Conclusions: Higher D2 receptor occupancy is associated with negative subjective experience in patients taking risperidone or olanzapine. These negative subjective effects may be related to the high discontinuation rates seen in usual practice. Understanding the neurobiological mechanism of these negative subjective experiences and developing antipsychotics with novel (i.e., non D2) mechanisms may be critical in improving the treatment of psychosis. [ABSTRACT FROM AUTHOR]

Abstract: The radioligand 3-(4-(3-[18F]fluoropropylthio)-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,5,6-tetrahydropyridine ([18F]FP-TZTP) is an agonist with specificity towards subtype 2 of muscarinic acetylcholine (M2) receptors. It is currently the only radiotracer available for imaging M2 receptors in human subjects with positron emission tomography. The present study reports on an improved method for the synthesis of [18F]FP-TZTP, automated using a GE TRACERlab™ FXFN radiosynthesis module. A key facet was the use of a new precursor, 3-(4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-3-ylthio)propyl 4-methylbenzenesulfonate. The precursor was fluorinated via nucleophilic displacement of the tosyloxy group by potassium cryptand [18F]fluoride (K[18F]/K222) in CH3CN at 80°C for 5min, and purified by HPLC. Formulated [18F]FP-TZTP was prepared in an uncorrected radiochemical yield of 29±4%, with a specific activity of 138±41GBq/μmol (3732±1109mCi/μmol) at the end of synthesis (35min; n=3). This methodology offers higher yields, faster synthesis times, an optimized precursor, and simpler automation than previously reported. [Copyright &y& Elsevier]

Abstract: Background: While antipsychotic-free schizophrenia patients showed a high degree of within-subject variability in dopamine D2 receptor density over 6–24 months, no study has examined the long-term stability of D2 receptor measures in medicated patients. Methods: Four schizophrenia patients receiving a stable dose of risperidone underwent [11C]raclopride positron emission tomography scans on two occasions 5–14 months apart. Results: Plasma risperidone levels were found to be consistent between scans, and consistencies of nondisplaceable D2 binding potential and D2 occupancy were good. Conclusions: The finding supports the validity of quantification of D2 receptor binding in longitudinal PET studies of medicated patients with schizophrenia. [Copyright &y& Elsevier]

Endogenous dopamine (DA) levels at dopamine D2/3 receptors (D2/3 R) have been quantified in the living human brain using the agonist radiotracer [(11) C]-(+)-PHNO. As an agonist radiotracer, [(11) C]-(+)-PHNO is more sensitive to endogenous DA levels than antagonist radiotracers. We sought to determine the proportion of the variance in baseline [(11) C]-(+)-PHNO binding to D2/3 Rs which can be accounted for by variation in endogenous DA levels. This was done by computing the Pearson's coefficient for the correlation between baseline binding potential (BPND ) and the change in BPND after acute DA depletion, using previously published data. All correlations were inverse, and the proportion of the variance in baseline [(11) C]-(+)-PHNO BPND that can be accounted for by variation in endogenous DA levels across the striatal subregions ranged from 42-59%. These results indicate that lower baseline values of [(11) C]-(+)-PHNO BPND reflect greater stimulation by endogenous DA. To further validate this interpretation, we sought to examine whether these data could be used to estimate the dissociation constant (Kd) of DA at D2/3 R. In line with previous in vitro work, we estimated the in vivo Kd of DA to be around 20 nM. In summary, the agonist radiotracer [(11) C]-(+)-PHNO can detect the impact of endogenous DA levels at D2/3 R in the living human brain from a single baseline scan, and may be more sensitive to this impact than other commonly employed radiotracers., (© 2016 Wiley Periodicals, Inc.)