Pharmacodynamics

• Partial agonist activity at D2 receptors
• Theoretically reduces dopamine output when dopamine concentrations are high, thus improving positive symptoms and mediating antipsychotic actions
• Theoretically increases dopamine output when dopamine concentrations are low, thus improving cognitive, negative, and mood symptoms
• Actions at dopamine 3 receptors could theoretically contribute to aripiprazole’s efficacy 
• Partial agonism at 5HT1A receptors may be associated with improvement in negative, cognitive, depressive, and anxiety symptoms
• Blockade of serotonin type 2A receptors may contribute at clinical doses to cause enhancement of dopamine release in certain brain regions, thus reducing motor side effects and possibly improving cognitive and affective symptoms
• Blockade of serotonin type 2C and 7 receptors as well as partial agonist actions at 5HT1A receptors may contribute to antidepressant actions

• By blocking alpha 1 adrenergic receptors, it can cause dizziness, sedation, and hypotension
• Mild block of H1 causing mild sedation and weight gain
• Partial agonist actions at dopamine 2 receptors in the striatum can cause motor side effects, such as akathisia
• Partial agonist actions at dopamine 2 receptors can also cause nausea, occasional vomiting, and activating side effects
• Mechanism of any possible weight gain is unknown; weight gain is not common with aripiprazole and may thus have a different mechanism from atypical antipsychotics for which weight gain is common or problematic
• Mechanism of any possible increased incidence of diabetes or dyslipidemia is unknown; early experience suggests these complications are not clearly associated with aripiprazole and if present may therefore have a different mechanism from that of atypical antipsychotics associated with an increased incidence of diabetes and dyslipidemia

• Blocks dopamine 2 receptors, reducing positive symptoms of psychosis and stabilizing affective symptoms; considering the idea that an antipsychotic needs to occupy 60% or more of D2 receptors in order to be clinically efficacious, quetiapine’s low D2 binding—typically approximately 30%—is noteworthy. However this seems to be due to rapid dissociation of Quetiapine from D2
• Blocks serotonin 2A receptors, causing enhancement of dopamine release in certain brain regions and thus reducing motor side effects and possibly improving cognitive and affective symptoms
• Interactions at a myriad of other neurotransmitter receptors may contribute to quetiapine’s efficacy in treatment-resistant depression or bipolar depression, especially 5HT1A partial agonist action, norepinephrine reuptake blockade and 5HT2C antagonist and 5HT7 antagonist properties
• Specifically, actions at 5HT1A receptors may contribute to efficacy for cognitive and affective symptoms in some patients, especially at moderate to high doses

In a series of studies, Kapur et al found that when D2 receptor occupancy with quetiapine was measured with positron emission tomography (PET) at shorter intervals (4 hours and 6 hours) than the conventional 12 hours after the last dose was taken, quetiapine did indeed show high D2 occupancy. They found that in contrast to other antipsychotics, quetiapine had a more rapid “run-off” from D2 receptors; that is, there was rapid dissociation of the D2 receptors (Kapur et al. 2000a). This was proposed to account for the discrepancy between observations of clinical potency and pharmacodynamic subthreshold receptor binding. This kiss-and-run theory is also put forward to explain the consistent observation of low rates of EPS and lack of increased prolactin levels during treatment with quetiapine (Nemeroff et al. 2002).

• By blocking histamine 1 receptors (strong) in the brain, it can cause sedation and possibly weight gain
• By blocking alpha 1 adrenergic receptors (strong), it can cause dizziness, sedation, and hypotension
• By blocking muscarinic 1 receptors, it can cause dry mouth, constipation, and sedation
• By blocking dopamine 2 receptors in the striatum, it can cause motor side effects (rare)
• Mechanism of weight gain and increased incidence of diabetes and dyslipidemia with atypical antipsychotics is unknown

• Blocks dopamine 2 receptors, reducing positive symptoms of psychosis and improving other behaviors
• One of the least potent D2 blockers (100 mg = 2 mg Haloperidol)
• Combination of dopamine D2, histamine H1, and cholinergic M1 blockade in the vomiting center may reduce nausea and vomiting

• By blocking dopamine 2 receptors in the striatum, it can cause motor side effects
• By blocking dopamine 2 receptors in the pituitary, it can cause elevations in prolactin
• By blocking dopamine 2 receptors excessively in the mesocortical and mesolimbic dopamine pathways, especially at high doses, it can cause worsening of negative and cognitive symptoms (neuroleptic-induced deficit syndrome)
• Anticholinergic actions may cause sedation, blurred vision, constipation, dry mouth
• Antihistaminic actions may cause sedation, weight gain
• By blocking alpha 1 adrenergic receptors, it can cause dizziness, sedation, and hypotension
• Mechanism of weight gain and any possible increased incidence of diabetes or dyslipidemia with conventional antipsychotics is unknown

• Blocks dopamine 2 receptors, reducing positive symptoms of psychosis and stabilizing affective symptoms; occupies lower percentage of D2(20-67%) than typicals (80%)
• Blocks serotonin 2A receptors, causing enhancement of dopamine release in certain brain regions and thus reducing motor side effects and possibly improving cognitive and affective symptoms
• High 5HT2A/D2 ratio like other SGA
• Acts on D4 (but no antipsychotic effects)
• Interactions at a myriad of other neurotransmitter receptors may contribute to clozapine’s efficacy
• Specifically, interactions at 5HT2C and 5HT1A receptors may contribute to efficacy for cognitive and affective symptoms in some patients
• Mechanism of efficacy for psychotic patients who do not respond to conventional antipsychotics is unknown

• Several explanations why clozapine is not associated with EPS
• 1. the lack of EPS with clozapine and other SGAs is related to their fast dissociation from the D2 receptor
• 2. Acute administration of conventional antipsychotic drugs to rodents leads to an increase in the firing of dopamine neurons in the substantia nigra and the ventral tegmental area. However, after 3 weeks of treatment with these agents, there is a decrease in the number of firing dopamine neurons in both of these areas. This prolonged decrease in firing has been referred to as depolarization inactivation. Inactivation in the ventral tegmental area has been used to explain the sustained therapeutic effectiveness of these agents, and inactivation in the substantia nigra has been used to explain EPS. Clozapine—together with other SGAs—causes inactivation in the ventral tegmental area, but not in the substantia nigra, suggesting that these agents have different effects in these two brain areas.