Antipsychotic advancements: The latest in antipsychotic psychopharmacology

The field of psychopharmacology is constantly evolving, especially in the past several years. It’s important to be aware of changes to stay updated in clinical practice. Over the past nine years eleven psychotropic agents have been added to the realm of treatment for various mood disorders, psychotic disorders, and Attention-Deficit/Hyperactivity Disorder.  

FDA novel psychotropic drug approvals since 2015 

In 2015: Aristada (long acting injectable that treats adults with schizophrenia), Vraylar (treats adults with schizophrenia and bipolar disorder), Rexulti (treats schizophrenia and adjunct to antidepressant treatment for major depressive disorder)

In 2016: Nuplazid (treats delusions and hallucinations associated with psychosis experienced by some individuals with Parkinson’s disease)

In 2017: Ingrezza (treats adults with tardive dyskinesia) 

In 2018: no novel psychotropic agents approved

In 2019: Caplyta* (treats schizophrenia) 

In 2020: no novel psychotropic agents approved

In 2021: Qelbree (treats ADHD, non-stimulant), Lybalvi (treats schizophrenia and certain aspects of bipolar I disorder), Azstarys (treats ADHD), Caplyta* (treats bipolar I and II depression in adults) 

In 2022: Auvelity (treats major depressive disorder in adults)

In 2023Zurzuvae (treats postpartum depression in adults) -more could be approved later this year!

*Notice that Caplyta is listed in two different years – it gained FDA approval for treatment of schizophrenia in 2019, and approval for treatment of bipolar I and II depression in adults in 2021.

Significant pharmacological advances have been made over the years for treatment of schizophrenia and bipolar disorder specifically, with the number of new medications created to treat these disorders. 

What’s so special about some of these newer psychotropic agents?

Not all, but many of the novel psychotropic agents developed over the past several years have a unique mechanism of action that makes them different from the agents that came before them. 

One commonality among some of these newer psychotropic agents is that many of them fall under a new class of antipsychotics: partial dopamine D2 receptor agonists. These agents combine D2 receptor agonism and partial agonism of other receptors.

Vraylar, Rexulti, Aristada, Lybalvi, Caplyta and Nuplazid are all partial dopamine agonists. 

How do partial dopamine agonists work?

Various mood and psychotic disorders are partially defined by imbalances of neurotransmitters in the brain – too much dopamine in certain areas of the brain, and too little dopamine in other areas of the brain, for example. 

Partial dopamine D2 receptor agonists work by balancing dopamine levels. In areas of the brain with too much dopamine, they partially block the activity of dopamine. In areas with too little dopamine, they increase dopamine activity. 

Older antipsychotic agents, such as first-generation antipsychotics, don’t balance dopamine levels but universally block dopamine activity. They differ from second-generation antipsychotics that also block serotonin activity. 

What’s helpful about partial dopamine agonists (sometimes called third-generation antipsychotics) is that they balance serotonin and dopamine activity. Aripiprazole (Abilify) was the first partial dopamine agonist, gaining FDA approval in 2002.

Why are partial dopamine D2 receptor agonists helpful medications?

1. Balance dopamine activity – dopamine system stabilization 

Like your favorite pair of jeans that fits just right in all the right places – tight in some areas, not tight in others – partial dopamine D2 receptor agonists are helpful because they stabilize dopamine. As previously discussed, in areas of the brain where there’s too much dopamine stimulation, these partial receptor agonists reduce excessive dopamine activity. Partial dopamine receptor agonists also enhance dopamine activity where levels are low. This balance is key because it helps address positive and negative symptoms of psychotic disorders and bipolar disorder

For example, typical antipsychotics help reduce positive symptoms of disorders such as schizophrenia by blocking dopamine (antagonize D2 receptors). The issue is that extrapyramidal side effects (EPS) are a common occurrence as a result of this blockade. 

Atypical antipsychotics targeting 5-HT2A and D2 receptors are more effective at addressing negative and cognitive symptoms compared to typical antipsychotics but these drugs also contribute to metabolic syndrome. 

Fortunately, partial dopamine D2 receptor agonists are helpful in that they are noted to have a lesser risk of metabolic side effects. This class of medications is a significant improvement on previous antipsychotic generations. 

2. Fewer extrapyramidal side effects and lower risk for tardive dyskinesia 

Another benefit of partial dopamine receptor agonists is that they result in fewer extrapyramidal side effects (EPS) and have a lower risk for tardive dyskinesia (TD). Great benefits. 

Because of their unique mechanism of action, these agents do not cause EPS that’s common among typical antipsychotics, which are dopamine receptor antagonists.  

Partial dopamine receptor agonists also have a lower risk of causing tardive dyskinesia compared to traditional antipsychotics. This is important to avoid because TD is a side effect associated with prolonged use of certain antipsychotic medications that can cause permanent involuntary movements. 

3. Improved negative symptoms 

Partial dopamine receptor agonists are also beneficial for improving negative symptoms. One of the challenges to treating psychotic disorders such as schizophrenia is treating negative symptoms – partial dopamine receptor agonists have demonstrated efficacy at reducing negative symptoms such as reduced emotional expression, lower motivation and social withdrawal. 

4. Adjunctive treatment for bipolar disorder 

This unique class of medications can also help effectively treat bipolar disorder. Some partial dopamine receptor agonists have been found to help with both manic and depressive episodes in individuals with bipolar disorder. These medications help to stabilize mood and reduce risk of relapse. 

Remember the basics. 

While the field of psychopharmacology is continuing to evolve with new and exciting advancements, it’s important to remember to keep in mind some of the basics too. 

Whenever starting a new medication, make sure to start with low doses and titrate carefully as you monitor your patient’s progress. Definitely address common concerns such as weight gain potential and akathisia with your patients so you can take a proactive approach and help your patients feel empowered in their treatment. Follow up with your patients regularly to ensure tolerance of medications and manage side effects. 

When rooted in the basics, you’re less likely to be overwhelmed as new medications are developed. This allows you to continue to provide high quality patient care and practice with confidence.  

If you’re looking for even more support on keeping updated with best practices for diagnosing and treating mental disorders, check out the Mental Disorders Crash Course.

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