Partial Dopamine Agonists: Receptor Profiles & Effects

• There are three marketed dopamine D2 partial agonists: aripiprazole, brexpiprazole, and cariprazine.
• These drugs share 5HT2 antagonism and D3 and 5HT1A partial agonism.
• They show minimal alpha-adrenergic, anticholinergic, or antihistaminic activity with a long duration of action.
• D2 partial agonists are effective antipsychotics with antimanic and antidepressant activity.
• These medications are usually well-tolerated, non-sedating, and carry a very low risk of increased prolactin levels, weight gain, and metabolic effects.
• There may be a relatively low risk of tardive dyskinesia.
• Patients may prefer dopamineD2 partial agonists to dopamine antagonists.
• Dopamine D2 partial agonists differ significantly from dopamine D2 antagonists and should be considered a distinct class of antipsychotics.

Schizophrenia

• Schizophrenia is a chronic psychiatric illness with a lifetime prevalence of just under 1% and an incidence of around 15 cases per 100,000.
• It is hypothesized to arise from a dysregulation of dopaminergic function
• Pharmacological treatments affect the dopamine system as receptor antagonists or partial agonists.
• Antipsychotic medications reduce relapses and mortality and increase quality of life.
• People with schizophrenia die 10-25 years earlier on average due to high suicidality, somatic diseases, metabolic syndrome, and treatment-associated adverse effects.
• First-line schizophrenia treatment involves second-generation or atypical antipsychotics like risperidone, quetiapine, olanzapine, and aripiprazole.
• The classification of antipsychotics depends on the propensity of an agent to cause acute movement disorders, reflecting affinity for dopamine D2 and serotonin 5HT2 receptors.
• Current antipsychotic medications have a relative risk for adverse events related to dopamine receptors antagonism, or activity at serotonin, muscarinic, alpha adrenergic and histaminergic receptors.
• Adverse events can cause non-adherence and long-term cardiovascular morbidity secondary to weight gain, metabolic dysregulation, and higher risk for cancers and osteoporosis due to hyperprolactinaemia.

Effective Antipsychotics

• There is an evident need for effective antipsychotics with a better tolerability profile.
• Dopamine partial agonists are emerging as a new class of drugs, called by some third-generation antipsychotics.
• Antipsychotic action is still primarily dependent on D2 receptors, achieved though weakening of the signal transmission and not full antagonistic blockade
• Other dopamine partial agonists, brexpiprazole and cariprazine, have been approved,
• This has made it more relevant to discuss these molecules as a group with shared properties, differentiating them from dopamine antagonists, both typical and atypical.
• It is important to compare dopamine partial agonists with dopamine antagonists, aiming to describe their properties and clinical application.

Partial Agonists

• FGAs like chlorpromazine and haloperidol effectively manage psychotic symptoms, but also cause extrapyramidal symptoms (EPS), TD, and hyperprolactinaemia, directly linked to dopamine blockade.
• FGAs do not address negative and cognitive symptoms and may deteriorate cognitive symptoms as soon as few days after initiation of treatment.
• SGAs act mostly through dopamine D2 receptor antagonism but show regional specificity and/or have affinity for serotonin receptors (5-HT2A).
• Antagonising 5-HT2A receptors raises dopamine neurotransmission in EPS-related brain areas (i.e. nigrostriatal system), thus reducing side effects (parkinsonism, dystonia, or akathisia).
• SGAs also have other side effects linked to serotonin, muscarinic, alpha adrenergic and histamine receptors, such as sedation and metabolic dysfunction and particularly weight gain.
• EPSE occurs at a relatively lower frequency than with FGAs, rather than not at all.
• Carlsson proposed the concept of dopamine receptor partial agonist, a drug that could act as agonist in some brain areas and as antagonist in others.
• Carlsson suggested activity depends on the magnitude the intrinsic dopaminergic activity.
• Partial agonists can bind to postsynaptic D2 receptors and act as antagonists, preventing excess dopamine from binding to receptor sites in the mesolimbic pathway.
• Binding of partial agonists effectively stimulates postsynaptic receptors thereby increasing cortical dopaminergic activity in the mesocortical pathway.
• Effective partial agonists modulate dopaminergic activity in competition with endogenous dopamine, with 20-30% activity of dopamine at the highest concentrations.
• This reduces the risk of side effects caused by near complete dopamine blockade.
• The affinity of all antipsychotic drugs for D2 receptors has to be higher than that of endogenous dopamine itself.
• The affinity of partial agonists for dopamine D2 receptors is generally higher than the affinity of dopamine antagonists.
• Striking the right balance between antagonism and intrinsic activity is very difficult.
• In particular, striking a balance avoids EPS and offers adequate antipsychotic efficacy
• Cariprazine and brexpiprazole were subsequently approved for clinical practice alongside aripiprazole.
• Therapeutic efficacy depends on reaching a certain threshold of antagonism rather than total blockade of all receptors.
• Occupancy is generally much higher as receptors have much higher dopamine receptor affinity than antagonists.
• At therapeutic doses, aripiprazole and cariprazine bind to over 90% of D2 receptors, having agonist action in low dopamine areas and antagonist actions in others.
• In the striatum, a partial agonist reduces the effect of high dopamine concentration, but not as completely as haloperidol
• In the prefrontal cortex, a partial agonist would provide a greater stimulus than the low-levels of endogenous dopamine.
• Pure dopamine antagonists block any signal transmission via the receptors, increasing both occupancy and blockade of D2 receptors so increasing the risk and severity of EPS
• With partial agonists, some intrinsic agonist activity always remains, protecting against emergent or worsening EPS.
• Thus a differentiator of partial agonists is their in vivo occupancy of D2 receptors at therapeutic doses and shows high efficacy.

Properties of Agonists

• The three marketed partial agonists share properties of high affinity partial agonism at D2, D3 and 5HT1A receptors combined with very low affinity antagonism at muscarinic and histaminic receptors
• The near absence of histamine H1 antagonism means that partial agonists are usually non-sedating and low activity at alpha-1 receptors indicates a low liability to cause postural hypotension.
• Small differences between individual partial agonists arise from variability in intrinsic activity and in affinity for various receptors.
• Aripiprazole has possibly the highest affinity for D2 receptors, but cariprazine and brexpiprazole have less intrinsic activity than aripiprazole.
• Partial agonists share the additional property of having high affinity at D3 receptors, which is hypothesised to be important in treating negative and cognitive symptoms of schizophrenia.
• Cariprazine has the strongest affinity for D3 of all the available partial agonists, with clinical supportive of its relevance in the management of both negative and cognitive symptoms.
• Only cariprazine demonstrates in vivo D3 receptor occupancy in human PET studies.
• Brexpiprazole has significantly higher affinity than aripiprazole or cariprazine with regard to serotonergic 5HT1A partial agonism and affinity for 5HT1A receptors
• These similarities inn pharmacological activities, show how agonists are consistent with chemically similarity of partial agonists
• Other un-marketed partial agonists such as aplindore, bifeprunox and OPC-4392 similarly share pharmacologoical properties

Agonists and Mood

• Strong D2 receptor antagonism is something of a blunt instrument compared with partial agonists,
• Blockade correlates with subjective well-being and negative affect and often causes dysphoria or inability to react to pleasurable things.
• Binding of aripiprazole to D2 receptors shows no correlation with changes in subjective well-being.
• All three partial agonists show partial agonism at 5HT1A receptors known to be antidepressant and have positive data for mood symptoms.
• Cariprazine also has some 5HT2B (presynaptic serotonin receptor) antagonism connecting it to depression relief and potentially substance use

Duration

• All available partial agonists have long plasma half-lives and all three generate active metabolites with long or even longer half-lives.
• Aripiprazole's main metabolite and cariprazine's metabolites are reportedly partial agonists
• Bifeprunox is the only D2 partial agonist compound with a relatively short half-life of around 9h.
• Clinical relevance is the fact that having a long half-life provides protection against relapse where compliance is erratic and assures a slow reduction in plasma levels when the drug is stopped.
• A long duration of action allows once-weekly supervised oral administration and allows protection for partially compliant patients.
• Once steady state is reached and where for cariprazine as much as two weeks passes for the receptor occupancy drop below therapeutic levels for medication use.
• Initiation with a low dose but with no unnecessary delay of dose increases gets rapid onset of effect- this is common and well-established in clinical practice

Tolerability

• A key advantage of partial agonist is their favorable tolerability and their low likelihood of dystonia, parkinsonism, weight gain, cardio-metabolic disturbance, hyperprolactinaemia and sexual dysfunction
• The most common adverse effect experienced with partial agonists is akathisia, transient and dose related
• Partial agonists generally do not cause sedation to adults
• It is notable that partial agonists seem to be relatively more sedative in younger people

Cardiometabolic

• Partial agonists tend not to cause diabetes or dyslipidemia and cause very limited weight gain if at all.
• The three partial agonists do not seem to prolong the cardiac QT interval to a clinically important degree and cariprazine and brexpiprazole show no dose-related effect on QTc.

EPS

• Partial agonists have a low liability for dystonia, parkinsonism and tardive dyskinesia but akathisia has been more commonly described
• Akathisia is probably more frequently observed with partial agonists than with some second-generation antipsychotics
• Akathisia is transient and responsive to either dose reduction or addition of a beta blocker
• When initiating consider from onset- adding on a beta blocker or a sedative agent

Prolactin and sexual dysfunction

• Partial agonists do not cause increased prolactin
• Cariprazine has been shown to normalize prolactin when used after prolactin-elevating drugs
• Partial agonists as a class tend not to produce sexual dysfunction and there are data on improvement when doing a drug switch
• There are other longer term, effects of high prolactin levels, such as osteoporosis and risk of cancer

Side Effect

• D2 partial agonists are more likely to be associated with impulse control disorders and induction or worsening of tics.

Efficacy of Agonists

• Dopamine antagonists, have a wide belief to be more effective then partial agonists in taking acute form.
• The claim has not been substantiated by reviews and there appear not to be a significance the effects with antipsychotic use.
• In the 1970s there was no signs of placebo effect , recent numbers show drugs do less well compared to placebo
• Marketed partial agonists include having negative symptoms with D3 receptors, with Cariprazine demonstrating superior efficacy versus risperidone from a direct comparsion
• Another is the lack of sedation associated with them

Considerations for Switching Agonists

• For reasons of tolerability, favorable long-term outcomes and functionality, this is often accompanied by concerns as switching to a partial agonist increases the risk of relapse.
• Clinical practice suggests attenuating potential problems when swithcing that arise with drugs with strong antihistaminergic and anticholinergic properties the dose of the sedative antagonist should be maintained until the partial agonist has been established
• During times of a switch the risk of discontinuation occurs high

Additional Information

• Important facts are often neglected from aspects in an acceptance of patient preference
• The patients treated with aripiprazole expressed higher amounts of positive views over treatment
• Most will say they are diagnosed for for aripiprazole preference for a partial agonist
• Patients often do not have sufficient information about options and side effects and tend to overwherlm clinicians skills
• Clinicians positive reflections can be mirrored by patient experience

Augmentation with partial agonists

• Augmentation is a less researched aspect of the use of antipsychotics but has a effect on additive aripiprazole when combined with other antagonists
• Addition does not improve overall response but some data suggests that there is a effect of cariprazine in negative symptoms and case of overall improvement
• Their drug of choice, polyphramcy agonists

Dopamine Supersensitivity

• It's is caused by antagonists with reduction in dose
• Agonist provides animal studeis and low risk

Discussion

• These are distinct agonists and low drug risks
• The 'pines' (clozapine, olanzapine, quetiapine) tend to be sedative and cause metabolic disturbance but have a low risk of prolactin elevation and EPS
• The 'dones' (risperidone, paliperidone, ziprasidone) are relatively less sedative, cause less weight gain, but are more likely to cause EPS and hyperprolactinaemia than 'pines'
• Partial can cause weight gain and hyperprolactinaemia. This is an observation to have partial agonists on negative symptoms.
• Tend to be used in a early position and are seen more in recent studies.
• Tend to be used treatment that occur more with primarily persistent negative symptoms
• Favorable to the short and long term.