Pharmacodynamics The<unk> s integrate with the serotonin (5-HT), norepinephrine (α, β), and dopamine (D) receptors in order to effectively treat schizophrenia. D2 Receptor: Hyperactive dopaminergic activity on D2 receptors in the mesolimbic pathway is responsible for the positive symptoms of schizophrenia (hallucinations, delusions, paranoia). After taking an<unk> , antagonism of D2 receptors occurs throughout the entire brain, leading to a number of deleterious side effects from D2 receptor antagonism throughout the entire dopamine pathway system. It's not possible to affect D2 receptors only in the mesolimbic pathway, but 5-HT2A receptor antagonism reverses these side effects to some extent. Reducing D2 dopaminergic activity in the mesolimbic pathway also results in an anhedonic effect, reducing pleasure and motivation. In the mesocortical pathway to the DLPFC and VMPFC, endogenous D2 receptor dopamine activity is sometimes low in schizophrenia, resulting in cognitive, affective, and, broadly, the negative symptoms of schizophrenia. D2 receptor antagonism further compounds these problems. In the nigrostriatal pathway, D2 receptor antagonism results in extrapyramidal symptoms. If this antagonism occurs long enough, symptoms of EPS may become permanent, even if<unk>  use is discontinued. In the tuberoinfundibular pathway, D2 receptor antagonism results in elevated prolactin. If prolactin levels become high enough, hyperprolactinaemia may occur, resulting in sexual dysfunction, weight gain, more rapid demineralization of bones, and possibly galactorrhea and amenorrhea. 5-HT2A Receptor: When serotonin is released on to postsynaptic 5-HT2A receptors, the dopamine neuron is inhibited, thus acting as a brake on dopamine release. This brake is disrupted through action of a 5-HT2A antagonist, which disinhibits the dopamine neuron, stimulating dopamine release. The result of this is that dopamine competes with<unk>  D2 antagonistic action at D2 receptors, thereby reducing antagonistic binding there and eliminating or lowering D2 antagonistic effects in several pathways of the dopamine system. In the nigrostratial pathway, it reduces EPS. In the tuberoinfundibular pathway, it reduces or eliminates prolactin elevation. Dopamine release in the mesolimbic pathway from 5-HT2A antagonism does not appear to be as robust as in the other pathways of the dopamine system, thereby accounting for why<unk> s still retain part of their efficacy against the positive symptoms of schizophrenia through their D2 antagonism. When 5-HT2A antagonistic agent particles occupy 5-HT2A receptors in the mesocortical pathway and in the prefrontal cortex, the negative symptoms of schizophrenia, affective symptoms, and cognitive deficits and abnormalities are treated and reduced. Furthermore, 5-HT2A receptor antagonism blocks the serotonergic excitation of cortical pyramidal cells, reducing glutamate release, which in turn lowers hyperactive dopaminergic D2 receptor activity in the mesolimbic pathway, reducing or eliminating the positive symptoms of schizophrenia. Some effects of 5-HT1A receptor activation include decreased aggressive behavior/ideation, increased sociability, and decreased anxiety and depression. 5-HT2C activation blocks dopamine and inhibits norepinephrine release. Blockade of the 5-HT2C receptor increases serotonin, releasing norepinephrine and dopamine within the brain. But neuronal reuptake of norepinephrine is limited sharply by some<unk> s, e.g. ziprasidone. Increased norepinephrine can cause increased glucose(blood sugar) levels. Increased blood sugar levels by increased norepinephrine causes hunger in many humans, which is why weight gain occurs with some<unk> s if the norepinephrine is not inhibited. Inhibition of norepinephrine stabilizes mood in humans. 5-HT6 receptor antagonists improve cognition, learning, and memory. The 5-HT7 receptor is very potent for the mitigation of bipolar conditions and also yields an antidepressant effect. The<unk> s asenapine, lurasidone, risperidone, and aripiprazole are very potent at the 5-HT7 receptor. Antagonistic affinity for the H1 receptor also has an antidepressant effect. H1 antagonism blocks serotonin and norepinephrine reuptake. Patients with increased histamine levels have been observed to have lower serotonin levels. However, the H1 receptor is linked to weight gain. To have partial agonism at the 5-HT1A receptor can yield absence of weight gain in an<unk> . This is very relevant for ziprasidone, but it creates a risk for a prolonged QTc interval. On the other hand, blockade of the 5-HT3 receptor removes the risk for a prolonged QTc interval, but then creates a larger risk for weight gain. Relation to the 5-HT3 receptor increases caloric uptake and glucose, which is seen in clozapine and olanzapine. Other ways for dopamine to resolve is to have agonism at both the D2 receptor and 5-HT1A receptor, which normalizes the dopamine level in the brain. This occurs with haloperidol and aripiprazole. Whether the anhedonic, loss of pleasure and motivation effect resulting from dopamine insufficiency or blockade at D2 receptors in the mesolimbic pathway, which is mediated in some part by<unk> s (and despite dopamine release in the mesocortical pathway from 5-HT2A antagonism, which is seen in<unk> s), or the positive mood, mood stabilization, and cognitive improvement effect resulting from<unk>  serotonergic activity is greater for the overall quality of life effect of an<unk>  is a question that is variable between individual experience and the<unk> (s) being used. Terms Inhibition. Disinhibition: The opposite process of inhibition, the turning on of a biological function. Release: Causes the appropriate neurotransmitters to be discharged in vesicles into the synapse where they attempt to bind to and activate a receptor. Downregulation and Upregulation. Binding profile Note: Unless otherwise specified, the drugs below serve as antagonists/inverse agonists at the receptors listed. Generic Name D1 D2 D3 D4 5-HT1A 5-HT1B 5-HT2A 5-HT2C 5-HT6 5-HT7 α1 α2 M1 M3 H1 Amisulpride - ++++ ++++ - - - - - - ++/+ - +/- - Aripiprazole + ++++ (PA) +++ (PA) + (PA) +++ (PA) + +++ ++ (PA) + +++ (PA) ++/+ + - - ++/+ Asenapine +++ +++ ++++ +++ +++ (PA) +++ ++++ ++++ ++++ ++++ +++ +++ - - +++ Blonanserin - ++++ ++++ + - ? +++ + + +/- + (RC) + (RC) + ? - Brexpiprazole ++ +++++ (PA) ++++ (PA) ++++ +++++ (PA) +++ +++++ +++ (PA) +++ ++++ - +++ Cariprazine ++++ (PA) +++++ (PA) ++++ (PA) +++ ++ ++ ++ - - +++ Clozapine ++ ++ ++ +++ ++ (PA) ++/+ ++++ ++++ +++ +++ ++++ +++ ++++ +++ ++++ Iloperidone + +++ +++ ++ + (PA) + +++ + ++ + ++++ +++/++ - - +++ Lurasidone + ++++ ++ ++ +++ (PA) ? ++++ +/- ? ++++ - +++/++ - Melperone ? ++ ++++ ++ + (PA) ? ++ + - ++ ++ ++ - - ++ Olanzapine +++ +++ +++ +++ + (PA) ++ ++++ +++ +++ ++ ++ ++ ++++ ++++ ++++ Paliperidone ++ +++ +++ ++ + (PA) +++/++ ++++ + - ++++/+++ +++ +++ - - +++/++ Quetiapine + ++/+ ++/+ + ++/+ (PA) + + + ++ +++/++ ++++ +++/++ ++ +++ ++++ Risperidone ++ +++ ++ +++ + (PA) ++ ++++ ++ - +++/++ +++/++ ++ - - ++ Sertindole ? +++ +++ +++ ++/+ (PA) ++ ++++ ++++ +++ ++ ++++/+++ + - - ++/+ Sulpiride ? ++++ ++++ +++ - - - - - - - - - Ziprasidone +++/++ +++ +++ +++/++ +++ (PA) +++ (PA) ++++ +++(PA) ++ +++ +++/++ ++ - - ++ Zotepine +++/++ +++ ++++/+++ +++ ++ (PA) +++ ++++ ++++ (RC) ++++ ++++/+++ +++ +++/++ ++ (RC) ++ (RC) ++++ Legend: No Affinity or No Data - Clinically Insignificant + Low ++ Moderate +++ High ++++ Very High +++++ Exceptionally High PA Partial Agonist RC Cloned Rat Receptor Pharmacokinetics<unk> s are most commonly administered orally.<unk> s can also be injected, but this method is not as common. They are lipid-soluble, are readily absorbed from the digestive tract, and can easily pass the blood–brain barrier and placental barriers. Once in the brain, the<unk> s work at the synapse by binding to the receptor.<unk> s are completely metabolized in the body and the metabolites are excreted in urine. These drugs have relatively long half-lives. Each drug has a different half-life, but the occupancy of the D2 receptor falls off within 24 hours with<unk> s, while lasting over 24 hours for the<unk> s. This may explain why relapse into psychosis happens quicker with<unk> s than with<unk> s, as the drug is excreted faster and is no longer working in the brain. Physical dependence with these drugs is very rare. However, if the drug is abruptly discontinued, psychotic symptoms, movement disorders, and sleep difficulty may be observed. It is possible that withdrawal is rarely seen because the<unk>  are stored in body fat tissues and slowly released. Drug Route(s) of Administration Half-life (t1/2 in hours) Volume of distribution (Vd in L/kg) Protein binding Excretion Enzymes involved in metabolism Bioavailability Peak plasma time (h) Cmax (ng/mL) Amisulpride Oral 12 5.8 16% Urine (50%), faeces (20%; 70% of this is as unchanged drug) ? 48% Two peaks: 1 hr & 3-4 hrs post-oral dosing 39±3 (1 hr), 54±4 (3-4 hrs) Aripiprazole Oral, intramuscular (including depot) 75 (94 for active metabolite) 4.9 99% Faeces (55%), urine (25%) CYP2D6 & CYP3A4 87% (Oral), 100% (IM) 3-5 ? Asenapine Sublingual 24 20-25 95% Urine (50%), faeces (40%) CYP1A2 & UGT1A4 35% (sublingual), 99.7% Urine (59%), faeces (30%) CYP3A4 84% (Oral) 60% 6
Atypical antipsychotic
Atypical antidepressant
Tricyclic antidepressant
Tetracyclic antidepressant
Heterocyclic antidepressant
Typical antipsychotic
Second-generation antidepressant
Antipsychotic