First-generation antipsychotics
Good morning! I wanted to talk about the first-generation antipsychotics and their history, so I hope you enjoy reading!
So, before the discovery of the first antipsychotic, chlorpromazine, aka Thorazine, treating psychosis, mania, and their related disorders (bipolar disorder (mania with or without psychosis or depression with psychosis), major depressive disorder with psychotic symptoms, schizophrenia, schizoaffective disorder, and others, treatment of these disorders was very difficult. I'm not gonna go too much into details, but I may append this post if people are interested.
Anyway, when chlorpromazine was tested and serendipidously found to drastically improve psychotic symptoms, it was a landmark in mental health treatment. It was initially tried as a sedative, since it had antihistamine effects and was therefore sedating, but they found that not only was the test patient sedated, but there was a profound improvement in his psychotic symptoms. After three weeks, he was able to be discharged from long-term hospitalization as he improved so drastically. There were many attempts to make other antipsychotic drugs that aimed to replicate chlorpromazine, which mainly included phenothiazines, which chlorpromazine is a member of. Other phenothiazines include methylene blue and promethazine.
Now, these antipsychotics were very effective, but later on, another serendipidous discovery of a different family of antipsychotics was discovered. Haloperidol, a butyrophenone, was far more potent than chlorpromazine by comparison, and despite having similar efficacy against delusions as chlorpromazine, it was significatly more effective at treating hallucinations and acute agitation than anything that was available at the time.
So, before the discovery of the first antipsychotic, chlorpromazine (discovered in the 1950s), aka Thorazine, treating psychosis, mania, and their related disorders (bipolar disorder (mania with or without psychosis or depression with psychosis), major depressive disorder with psychotic symptoms, schizophrenia, schizoaffective disorder, and others, treatment of these disorders was very difficult. I'm not gonna go too much into details, but I may append this post if people are interested.
Anyway, when chlorpromazine was tested and serendipidously found to drastically improve psychotic symptoms, it was a landmark in mental health treatment. It was initially tried as a sedative, since it had antihistamine effects and was therefore sedating, but they found that not only was the test patient sedated, but there was a profound improvement in his psychotic symptoms. After three weeks, he was able to be discharged from long-term hospitalization as he improved so drastically. There were many attempts to make other antipsychotic drugs that aimed to replicate chlorpromazine, which mainly included phenothiazines, which chlorpromazine is a member of. Other phenothiazines include methylene blue and promethazine.
Now, these antipsychotics were very effective, but later on, another serendipidous discovery of a different family of antipsychotics was discovered. Haloperidol, a butyrophenone, was far more potent than chlorpromazine by comparison, and despite having similar efficacy against delusions as chlorpromazine, it was significatly more effective at treating hallucinations and acute agitation than anything that was available at the time.
Next, I will describe the mechanism of antipsychotics. While it's not exactly clear *why* these work, it is evident that a major contributor to the antipsychotic effects was its ability to block certain dopamine receptors, namely the dopamine D2 receptor, which is highly implicated in psychosis. It is believed that, for optimal antipsychotic effects in the first-generation, you should aim for between 60% and 80% occupancy of the dopamine D2 receptors in the brain. The lower, the better, as it will reduce side effects (which I will get to later on), assuming its still effective.
There are different levels of potencies that are described in first-gen antipsychotics. These include the low potency (clorpromazine), middle potency (perphenazine), and high potency (haloperidol, fluphenazine) drugs. The low potency has a low risk for extrapyramidal side effects caused by dopamine blockade (I will get to EPS later), but had a larger range of side effects. These included effects on histamine (drowsiness), (nor)adrenergic (orthostatic hypertension), muscarinic (dry mouth, constipation). Typical daily doses of low potency drugs are high at around 300 mg per day.
High potency, on the other hand, has more selective binding to the dopamine D2 receptors specifically and usually have much lower effects on other systems. However, it has a high risk of anti-dopamine side effects, most notably extrapyramidal symptoms (EPS). These symptoms include dystonia, which is uncontrolable muscle movements which can be painful, akathisia, which causes profound restlessness, parkinsonism, which causes symptoms resembling what you would find in people suffering from parkinson's disease (muscle rigidity/stiffness, bradykinesia (moving slowly), tremor (shaking), and postural instability (difficulty with balance and coordination).
However, the most concerning side effect is tardive dyskinesia, which causes continuous involuntary movements of muscles, mainly facial muscles. This can look like opening and closing your mouth while moving your jaw in a circular motion, sticking out your tongue, and moving your lips around. These movements cannot be controlled. The tardive aspect refers to its development after continuous use of the drugs, which can cause drug-induced brain injury. Tardive dyskinesia is usually treated by stopping the antipsychotic (slowly), but sometimes the damage can be permanent.
Other non-motor side effects include hyperprolactinemia. Prolactin secretion is usually inhibited by dopamine, but when it is blocked, it can limit your brain's ability to control it. Also, it can worsen symptoms of poor motivation, anhedonia, flat affect, and diminished speech.
After many years, they eventually developed the second-generation of antipsychotics, which greatly improved the risk of EPS and the permanent tardive dyskinesia.
Let me know if you want me to add anything! Thanks for reading, and be well!
š° AsherFisc [mod, Psychiatry nerd and pharmacology enthusiast.]
2025-02-23 Ā· 1 year ago Ā· š stack, murdock
2 Comments ā
š undefined Ā· 2025-02-24 at 05:23:
One of the guys I knew was in the mental facilities, kind of intermittently as a lot of people seem to be. I don't know his exact diagnosos, but it was pretty bad, he had hallucinations, oftentimes felt like someone was controlling his actions and thoughts, manic states as well if I recall correctly. Absolutely hated these, as, again, lots of people seem to. The way he described it is, it just turns you into a zombie. Where as, normally the problem would be that he'd think too much and get into these rabbit holes of delusion, what the antipsychotics would do is just make him unable to think whatsoever, which is not ideal to say the least.
And the whole carousel of side effects was pretty brutal as well. Basically you'd get prescribed one thing, but that might have side effects so to counter those something else would need to be prescribed and so on.
š° AsherFisc [OP/mod, Psychiatry nerd and pharmacology enthusiast.] Ā· 2025-02-24 at 12:15:
I was prescribed an antipsychotic, and I donāt think itās bad as a lot of people make it out to be. A lot of it comes down to finding one that you can tolerate and works for you, and thereās more now than there used to be. Some newer options arenāt as strong dopamine antagonists and they are have effects on serotonin as well, which certain serotonin antagonists have been shown to alleviate the dopamine antagonistsā side effects. Thereās hope. Hopefully they will advocate for themselves and find the best solution possible.