These findings indicate that dopamine overactivity predates the onset of schizophrenia in individuals with prodromal psychotic symptoms, is predominantly localized in the associative striatum, and is correlated with the severity of symptoms and neurocognitive dysfunction.

Therapeutic drug monitoring studies have generally concentrated on controlling compliance and avoiding side effects by maintaining long-term exposure to minimally effective blood concentrations. The rationale for using therapeutic drug monitoring in relation to second-generation antipsychotics is still being discussed at least with regard to the real clinical utility, but there is evidence that it can improve efficacy, especially when patients do not respond or develop side effects using therapeutic doses. Furthermore, drug plasma concentration determinations can be of some utility in medico-legal problems. This review concentrates on the clinical pharmacokinetic data related to clozapine, risperidone, paliperidone, olanzapine, quetiapine, amisulpride, ziprasidone, aripiprazole, sertindole, asenapine, iloperidone, lurasidone, brexpiprazole and cariprazine and briefly considers the main aspects of their pharmacodynamics. Optimal plasma concentration ranges are proposed for clozapine, risperidone, paliperidone and olanzapine because the studies of quetiapine, amisulpride, asenapine, iloperidone and lurasidone provide only limited information and there is no direct evidence concerning ziprasidone, aripiprazole, sertindole, brexpiprazole and cariprazine: the few reported investigations need to be confirmed and extended.

Objective-Whilst there is robust evidence of elevated dopamine synthesis capacity once a psychotic disorder has developed, little is known about whether it is altered prior to the first episode of frank illness. We addressed this issue by measuring dopamine synthesis capacity in subjects at ultra high risk of psychosis, and then following them to determine their clinical outcome.Method-This prospective study included thirty subjects who met standard criteria for being at ultra high risk of psychosis and twenty-nine healthy volunteers. Subjects were scanned using [18F]-DOPA positron emission tomography. The ultra high risk subjects were scanned at presentation and followed-up for at least three years to determine their clinical outcome. Six subjects had co-morbid schizotypal personality disorder and were excluded from the analysis (data are provided for comparison). Of the remaining subjects, nine developed a psychotic disorder subsequent to scanning (psychotic transition group), and 15 did not (non-transition group).Results-There was a significant effect of group on striatal dopamine synthesis capacity (p=0.006). The psychotic transition group had greater dopamine synthesis capacity in the striatum (p=0.004, effect size=1.18) and its associative subdivision (p=0.015, effect size=1.24) than controls, and showed a positive correlation between dopamine synthesis capacity and symptom severity. Dopamine synthesis capacity was also significantly greater in the psychotic transition than the non-transition group (p=0.036).Conclusions-These findings provide evidence that the onset of frank psychosis is preceded by presynaptic dopaminergic dysfunction. Further work is required to determine the specificity of elevated dopamine synthesis capacity to particular psychotic disorders.

Background: The glutamate model of schizophrenia proposes that altered glutamatergic neurotransmission is fundamental to the development of the disorder. In addition, its potential to mediate neurotoxicity raises the possibility that glutamate dysfunction could underlie neuroanatomical changes in schizophrenia. Here we determine whether changes in brain glutamate are present in subjects at ultra high risk of developing psychosis, and whether these changes are related to reductions in cortical gray matter volume.Methods: Twenty-seven individuals with an At Risk Mental State (ARMS) and a group of 27 healthy volunteers underwent proton magnetic resonance spectroscopy and volumetric proton magnetic resonance imaging using a 3 Tesla scanner.Glutamate and glutamine levels were measured in anterior cingulate, left hippocampus and left thalamus. These measures were then related to cortical gray matter volume.Results: ARMS subjects had significantly lower levels of glutamate than controls in the thalamus (p<0.05), but higher glutamine in the anterior cingulate (p<0.05). Within the ARMS group, the level of thalamic glutamate was directly correlated with gray matter volume in the medial temporal cortex and insula (p<0.01). Conclusions:This study provides the first evidence that brain glutamate function is perturbed in people with prodromal signs of schizophrenia, and that glutamatergic dysfunction is associated with a reduction in gray matter volume in brain regions thought to be critical to the pathogenesis of the disorder. These findings support the hypothesis that drugs affecting the glutamate system may be of benefit in the early stages of psychotic illness.