Transcript:
TA: Hello and welcome! I am Alan Amberg, a psychiatric mental health nurse practitioner, but you can call me Tony.
PM: And I am Dr Pradeep Manudhane, a clinical assistant professor at Northeast Ohio Medical University and a community mental health psychiatrist at Phoenix Rising in Canton, Ohio. Thank you for joining Tony and me as we explore the history and evolution of a class of medication known as antipsychotics.
TA: Pradeep, did you know that the first antipsychotic was discovered by accident when it was used as a surgical anesthetic?
PM: Yes, it’s a fascinating story. The first antipsychotic was serendipitously discovered in 1951 by a French surgeon, Henri Laborit. He noticed that when a phenothiazine was administered to augment the effects of surgical anesthesia, the patients did not lose consciousness yet showed a lack of interest in their surroundings.1
TA: Indeed. This was followed by a subsequent observation by psychiatrists Jean Delay and Pierre Deniker in 1952. They observed that a phenothiazine had calming effects on the symptoms of psychosis, such as hallucinations and delusions, in patients with mania or schizophrenia.1-3 This ultimately led to the birth of the nomenclature “antipsychotic.”3
PM: Over the next few years, psychiatrists pioneered the use of antipsychotics in managing the symptoms of schizophrenia patients.4 As you know, Tony, before antipsychotics were discovered, the standard treatments for schizophrenia were invasive therapies such as electroconvulsive therapy, insulin coma, and frontal lobotomy.2 These procedures were not only invasive, but they also carried serious risks that negated their overall benefits.4
TA: That’s right, Pradeep. The initial class of antipsychotics made it possible for us to treat schizophrenia with oral agents rather than invasive procedures, and this allowed patients with schizophrenia to have more management options.4
PM: After the discovery of the initial antipsychotics, development of similar compounds followed in the 1950s to the 1970s, giving rise to what are better known as first-generation antipsychotics, or FGAs.5
TA: Pradeep, as you know, FGAs, also referred to as “typical” antipsychotics, are thought to work by primarily antagonizing dopamine D2 receptors.5,6 Notably, the rise of FGAs was accompanied by the thought that dopamine hyperactivity may underlie the pathogenesis of schizophrenia.5 Therefore, by antagonizing D2 receptors, FGAs were hypothesized to help reduce the positive symptoms of schizophrenia such as delusions and hallucinations.5,6
PM: Tony, we know that while blocking D2 receptors with FGAs may help with the schizophrenia symptoms, it may also potentially result in adverse effects. For example, FGAs have been associated with extrapyramidal symptoms, or EPS, including Parkinsonism, acute dystonia, akathisia, and tardive dyskinesia.5,6 In fact, at one point, prescribers actually believed that the motor dysfunctions were a sign of the medication working!2
TA: That’s right, Pradeep. In an effort to help mitigate potential side effects, second-generation antipsychotics, or SGAs, were investigated and developed.
PM: Tony, as you know, SGAs, also known as “atypical” antipsychotics, are thought to target a range of dopamine and serotonin receptors.5
TA: Yes, and why do we now go after the serotonin receptors? We observed in animal studies that several hallucinogenic compounds function as 5-HT2A full agonists. So, the hypothesis became that 5-HT2A partial agonists or antagonists may be antipsychotic in action.7
PM: During the clinical trials for schizophrenia, SGAs were observed to also have antimanic, mood-stabilizing, and antidepressant effects. This observation led to other clinical trials studying their potential use in the treatment of psychiatric conditions, such as the adjunctive use in major depressive disorder, or MDD, and bipolar disorder, or BP.6,8 And now, SGAs are a part of the psychiatry treatment landscape.5,6
TA: One thing to remember about SGAs is that they may help mitigate EPS by targeting dopamine and serotonin receptors, whose interactions are thought to lead to a reduced D2 blockade. However, due to the range of receptors they target, this may lead to other potential side effects.5,9
PM: That’s right, Tony. SGAs can be associated with metabolic side effects5 such as weight gain,10 and alterations in cholesterol production11 and glucose metabolism.12 Therefore, the search continued for additional mechanisms.
TA: Yes, and this gave rise to dopamine partial agonists, which added to the treatment landscape in psychiatry.5,6 It is thought that mechanistically, depending on the endogenous dopamine levels, dopamine partial agonists may partially activate or inhibit dopamine receptors. This may explain their utility in psychiatric conditions and may play a role in their side effect profiles.5 In terms of safety, we should note that although few movement disorders may be observed with partial agonists, they may still occur with the use of these treatments.13
PM: As we discussed, antipsychotics are a class of medication originally used to treat psychosis associated with schizophrenia.4-6 However, aside from their initial use in treating schizophrenia, they have also been discovered as management options for psychiatric conditions, including bipolar disorder and in adjunctive MDD.6,14
TA: Absolutely, Pradeep. Expanding our understanding of neurotransmitter mechanisms allowed us to hypothesize that antipsychotics may play a role in psychiatric disorders beyond schizophrenia and evolve into management options for a range of psychiatric disorders, including bipolar and MDD. Yet, there are still barriers to using antipsychotics, wouldn’t you say?
PM: Indeed, Tony. Antipsychotic medications, whether FGAs, SGAs, or partial agonists, may cause the aforementioned side effects.15 If they are not properly managed, these side effects can lead to decreased adherence, which may be perceived by the patient as the medication being ineffective.
TA: That is true. A systematic literature review of studies from 1990 to 2015 inclusive of patients with schizophrenia and bipolar disorder showed that adherence to antipsychotics could range from 34% to 81%.16
The high rates of non-adherence with antipsychotics highlight the importance of selecting a medication that is personalized to the patient.16
PM: That’s a good point, Tony. Another major barrier to choosing antipsychotics as a management option for bipolar or major depressive disorder comes from the stigma associated with the name, “antipsychotics.” Despite clinical evidence supporting antipsychotic use in BP and adjunctive use in MDD, there continues to be social stigma in patients who are prescribed antipsychotics.17
TA: I agree, Pradeep. Remember that a medication often takes its classification from its first indicated use. Today, we can use medications that were classified as anticonvulsants and antihypertensives in psychiatry, but nobody calls them that in our office. So, it’s really important to educate patients that the “classification of a medication” may not always be the same as its current use in that patient. In fact, the “classification” may even be misleading.18
This stigma can cause patients to be upset and may prevent them from seeking treatment altogether or adhering to their prescribed medication.17
PM: Tony, what about the stigma from the perspective of the provider? Some providers may be hesitant to prescribe medications called “antipsychotics” even though there is evidence showing their efficacy in addressing the symptoms of the psychiatric condition that they are trying to manage.17
TA: That is very true, Pradeep. That is why I believe educating both patients and providers on the history of the discovery and iterations of modern antipsychotics is important in helping to reduce this stigma.
PM: Yes. I also think that raising awareness among patients and providers about antipsychotics has shown to be effective in addressing symptoms of bipolar disorder and as an adjunctive therapy for major depressive disorder, not just psychosis. It may help us all understand the broader application of antipsychotics and their psychopharmacology.
TA: Absolutely. As we have discussed today, since its discovery, the antipsychotic class has evolved, broadening its indications in a range of psychiatric conditions, including schizophrenia, BP, and adjunctive use in MDD.
PM: Yet, there is still work to be done to help overcome the stigma associated with antipsychotic use through patient and provider education. Lastly, it is important to remember that individuals can react differently to the same medication, and having a range of therapeutic options available can be beneficial.
TA: Thank you, Pradeep, for joining me today in this fascinating look at the history and evolution of antipsychotics.
PM: It’s been a pleasure, Tony. And we want to thank you, our listeners, for joining us on NP Psych Navigator!
