No clear mechanism is implicated, but it has been hypothesized that it has something to do with abnormal mitochondrial respiration due to the uncoupling of oxidative phosphorylation.Other side effects regard the increase in dopaminergic activity, including digestive symptoms. Treatment with tolcapone runs the risk of eliciting or prolonging dyskinesia; this can be counteracted by decreasing the dose of levodopa. This occurs because the administration of tolcapone results in the accumulation of the biological methyl donor S-adenosyl-L-methionine (SAM) in the striatum that induces Parkinson symptoms.Digestive symptoms include nausea and diarrhea; further dopaminergic side effects include orthostatic hypotension, dry mouth, sweating and dizziness. Tolcapone causes more severe diarrhea than entacapone; this was the most common reason for therapy termination in studies. Urine discoloration comes from yellow tolcapone metabolites being excreted in the urine and is harmless. Interactions
While increase of dopamine levels is a desired interaction, tolcapone can theoretically also increase the levels of other drugs metabolised by COMT, such as the AADC inhibitors carbidopa and benzerazide, as well as methyldopa, dobutamine, apomorphine, adrenaline, and isoprenaline. In studies, a slight interaction with benzerazide was seen, but not with carbidopa. Other interactions with this group of drugs have not been studied. A related type of theoretical interactions is with drugs that increase catecholamine concentrations, such as monoamine oxidase (MAO) inhibitors and noradrenaline reuptake inhibitors; these also showed only slight effects in practice.
Cariprazine also acts on 5-HT1A receptors, though the affinity is considerably lower than the affinity to dopamine receptors (seen in monkey and rat brain studies). In the same studies, cariprazine has been noted to produce pro-cognitive effects, the mechanisms of which are currently under investigation. An example of pro-cognitive effects occurred in pre-clinical trials with rats: rats with cariprazine performed better in a scopolamine-induced learning impairment paradigm in a water labyrinth test. This may be due to the selective antagonist nature of D3 receptors, though further studies need to be conducted. This result could be very useful for schizophrenia, as one of the symptoms includes cognitive deficits. Cariprazine has partial agonist as well as antagonist properties depending on the endogenous dopamine levels. When endogenous dopamine levels are high (as is hypothesized in schizophrenic patients), cariprazine acts as an antagonist by blocking dopamine receptors. When endogenous dopamine levels are low, cariprazine acts more as an agonist, increasing dopamine receptor activity. In monkey studies, the administration of increasing doses of cariprazine resulted in a dose-dependent and saturable reduction of specific binding. At the highest dose (300 μg/kg), the D2/D3 receptors were 94% occupied, while at the lowest dose (1 μg/kg), receptors were 5% occupied. Dopamine D2 and D3 receptor occupancy in humans has been summarized as, "In healthy volunteers, single-dose cariprazine of 0.5 mg occupied up to 12% of striatal D2/D3 receptors, while striatal D2/D3 occupancy after multiple dosing up to cariprazine 1.0 mg/d ranged from 63 to 79% [39].