Dopamine activity in the PFC and striatum
Dopamine activity in the PFC and striatum may be antagonistic, meaning that lower levels of dopamine in the striatum tend to correspond to higher levels of dopamine in the PFC and vice versa (Cools and D\'Esposito, 2011; Tunbridge et al., 2006). Human PET studies have reported that dopaminergic PFC function may reflect modulation of the frontostriatal network, which varies as a function of basal dopamine concentrations in the striatum rather than the PFC (Cools and D\'Esposito, 2011). This may help explain why antagonism of striatal DA receptors would have cognitive effects associated with COMT, which is a significant regulator of DA disposition within the PFC. The present findings are also consistent with the dual state model of PFC DA function (Durstewitz and Seamans, 2008), which predicts that schizophrenia is characterized by a low baseline DA state in Val homozygotes and a moderate baseline DA state in Met carriers (Durstewitz and Seamans, 2008). Specifically, this model predicts too much or too little D2 activation leads to highly unstable representations of behavioral response preferences. Therefore, antipsychotic medication may push Val homozygotes to a lower D2 activation state leading to impairments in cognitive stability.
An “inverted-U” is widely believed to characterize the relationship between dopaminergic activity and cognitive performance, in which too much or too little dopaminergic activity has detrimental effects on cognition (Sawaguchi and Goldman-Raikic, 1991). The present findings were consistent with the hypothesis that FEP patients that carry two Val ENMD-2076 have striatal dopaminergic activity near or below the optimal range prior to treatment that was lowered following antipsychotic treatment to a level that impaired cognitive performance. In contrast, participants with one or more MET alleles may have more moderate DA states at baseline than their Val homozygote counterparts (Durstewitz & Seamans, 2008) and antipsychotic treatment may have lowered elevated DA activity to more optimal levels for transitioning between cognitive stability and flexibility, thus leading to robust improvements in both areas. Additionally, antipsychotic medication may enhance dopamine tone in the cortex as a downstream effect of striatal antagonism, yet increased prefrontal dopamine may be negated by high enzyme activity associated with the Val allele, thus preventing improvements in cognitive flexibility.
The present findings were consistent with the notion that dopamine activity modulates cognitive processing, particularly perseveration in first episode schizophrenia (Szeszko et al., 1999). Several prior studies have failed to identify robust cognitive changes associated with antipsychotic treatment (Keefe et al., 2007; Hill et al., 2010). This might be related to the limited utility of standard clinical neuropsychological measures to detect antipsychotic medication effects due to the cognitive complexity that yields many neuropsychological measures sensitive but not specific (Hill et al., 2008; Reilly and Sweeney, 2014). The present translational approach of subtyping set-shifting errors based on preclinical rodent research models may have provided the necessary specificity to reveal genotype-specific profiles of individuals receiving beneficial and adverse cognitive effects from antipsychotic medications, as has been the case for translational models assessing antipsychotic effects on working memory (Reilly et al., 2006, Reilly et al., 2007).
Introduction Depression is one of the most common mood disorders. Major depressive disorder (MDD) is highly prevalent in the general population. Approximately 1 person in 5 may undergo it in their lifespan. MDD is almost twice as predominant in women than men (Fava and Kendler, 2000, Picco et al., 2017). In Taiwan, the prevalence of MDD among the elder is higher than the reported rate from western countries (Chong et al., 2001). Recent numbers report it at around 1.5% in older community-dwelling adults (Wu et al., 2017). MDD is increasing and extending into younger generations. Abnormal prefrontal-limbic interactions and altered catecholaminergic neurotransmission are rationalized as parts of MDD etiology (Seok et al., 2013). Several clinical and genomic association studies suggested that the catechol-O-methyltransferase (COMT) gene is an important genetic locus modulating susceptibility to psychiatric disorders (Kocabas, 2012, Taylor, 2018). COMT is the central enzyme in the catabolic pathway of catecholamine neurotransmitters including dopamine, epinephrine, and norepinephrine. Therefore, COMT has been proposed to play a role in mood regulation, based on the “chemical imbalance” theory for depression (Kessler et al., 2003, Schildkraut, 1965), which suggested that diminished levels of monoamine neurotransmitters might enhance the risk for depression.