Welcome to the second post of my psych meds 101 series on how psychiatric medications work, this time focusing on antipsychotics. In these posts, I’m bringing together my knowledge as a mental health nurse, ex-pharmacist, and gal with depression who’s tried a boatload of meds, and hopefully putting out something that will make it easier to understand the nuts and bolts underlying the meds that so many of us take. Knowledge is power, after all.
**Note: This post will exclusively use generic drug names, since brand names vary from country to country.
Needless to say, the primary use of antipsychotic medications is in the treatment of psychosis. However, they also have other uses, much like antidepressants are used in conditions other than depression. The names antipsychotic and antidepressant make for convenient categorical labels, but what’s actually relevant therapeutically is how they affect neurotransmitters.
Atypical antipsychotics have an important role to play as mood stabilizers in bipolar disorder and to augment antidepressant regimens in major depressive disorder. They may also be used for anxiety, and quetiapine is a common example of this. Sedating antipsychotics, such as quetiapine and the older drug methotrimeprazine, may be used for sleep. Haloperidol, a typical antipsychotic, is also used in the treatment of delirium, which involves a rapid-onset disturbance in cognition and orientation.
How antipsychotics work
Antipsychotics work by blocking D2 dopamine receptors. This impacts four major dopamine pathways in the brain, producing the therapeutic effect as well as side effects:
- mesolimbic: dopamine overactivity in this pathway is associated with psychotic symptoms
- mesocortical: this affects areas of the prefrontal cortex (the most evolutionarily advanced part of the brain) associated with cognition and mood
- nigrostriatal: this pathway is associated with movement
- tuberoinfundibular: this pathway regulates the hormone prolactin
There are two broad classes of antipsychotics: the “typicals” (older) and “atypicals“. The key difference between these classes is that atypicals also block 5HT2a serotonin receptors. This actually boosts dopamine signalling in the pathways other than the mesolimbic, which decreases the risk of side effects related to those 3 pathways. Additionally, the effect on 5HT2a receptors contributes to a therapeutic effect on mood.
Another difference is that the atypicals are thought to move more rapidly on and off the D2 receptors, which is thought to allow for the full therapeutic effect without as much potential for side effects (this effect is referred to as “hit-and-run”).
To complicate matters, most antipsychotics aren’t very “clean”, in that they affect a number of other receptors aside from D2 and 5HT2a. And that means side effects.
There’s no way to predict which specific person is going to experience which particular side effects and whether or not those side effects will be tolerable. In general, though, medication side effect profiles are based on the types of receptors they interact with.
Extrapyramidal symptoms (EPS) occur most commonly with typical antipsychotics. These are named for an area of the brain that is part of the nigrostriatal dopamine-signalling pathway. Excessively blocking dopamine in this region produces movement-related side effects, including tremor, rigidity, and akathisia (restlessness). Anticholinergic medications such as benztropine can help to reverse these symptoms, due to an inverse relationship between the neurotransmitters acetylcholine and dopamine in this part of the brain.
Tardive dyskinesia (TD) is a slow onset, potentially reversible involuntary movement disorder that may affect the mouth, hands, and trunk. It is caused by enduring changes in dopamine receptors in the basal ganglia as a result of long-term use of high-potency typical antipsychotics. The risk of TD with atypicals is very low, and clozapine may actually improve TD symptoms.
Dopamine blockade in the tongue-twisting tuberoinfundibular pathway can increase levels of the hormone prolactin, which can result in some distressing side effects. It can affect both sex drive and sexual function, and can also cause gynecomastia (development of breast tissue in men). In general, atypicals are less likely to cause this, although risperidone tends to carry a higher risk than other atypicals.
The atypicals win out over the typicals in many senses, but a major downside is that they do carry a risk for metabolic syndrome, including weight gain, increased cholesterol, and increased diabetes risk. This may be related to activity at histamine and 5HT2c serotonin receptors. The big three are clozapine, olanzapine, and (to a lesser extent) quetiapine. Aripiprazole and ziprasidone do not tend to be associated with weight gain.
This can be related to effects on histamine, muscarinic, and alpha-adrenergic receptors. Individual medications vary in terms of which of these receptors they do or don’t affect, so there is a lot of variability in sedating effect.
The cholinergic signalling system is responsible for resting and digesting activities. When antipsychotics disrupt this, the result can be things like dry mouth and constipation. On a more positive note, this can decrease the likelihood of experiencing EPS. Again, there’s a lot of variation from medication to medication as to anticholinergic activity.
Drugs in this class
Atypicals are often used as mood stabilizers in bipolar disorder or as antidepressant augmentation in depression. There’s variability in side effects among the different medications, so just because one drug causes particular side effects doesn’t mean that another necessarily will.
Some common examples in this class include:
- aripiprazole (Abilify)
- brexpiprazole (Rexulti)
- cariprazine (Vraylar)
- clozapine (Clozaril)
- olanzapine (Zyprexa)
- paliperidone (Invega) – closely related to risperidone
- quetiapine (Seroquel)
- risperidone (Risperdal)
- ziprasidone (Geodon)
Risperidone and aripiprazole tend to be more likely to cause movement-related side effects. Ziprasidone has a low likelihood of weight gain, while the risk of weight gain is high with olanzapine.
Clozapine is an atypical antipsychotic that can be an absolute wonder drug for people whose psychotic symptoms are resistant to other medications. It is the only antipsychotic that has been shown to decrease the risk of suicide in schizophrenia.
However, it can be problematic in terms of side effects. It can increase the risk of seizures. It can cause drooling, which can be quite bothersome for some people. Of greater concern, it can cause a dangerous drop in white blood cells, so bloodwork is required every 1-4 weeks (there’s more on this in the Quick Guide to Lab Tests on the Resources page). When starting clozapine, there is a small risk of an inflammatory reaction in the heart called myocarditis.
Clozapine is definitely not a first-line medication, but sometimes you really do need to bring out the big guns, and this medication is a go-to on refractory psychosis wards.
Examples include loxapine, haloperidol, zuclopenthixol, and flupenthixol. The latter three are often given as long-acting injections, although there are more alternatives now as a number of atypicals have become available for injection.
There are a number of typical and antitypical medications available as long-acting (“depot”) injections, including aripiprazole, risperidone, and paliperidone. These are generally given every 2-4 weeks. They are given intramuscularly into the shoulder (deltoid), hip (ventrogluteal) or upper buttocks (dorsogluteal) sites.
There are a number of benefits to long-acting injections. For some people, it’s just easier to get an injection every few weeks than to take pills every day. Long-acting injections produce very steady levels of medication in the blood, and it can be hard to replicate this even if someone is fairly consistent with taking oral medications.
The downside to long-acting injections is that if people have side effects, they have to wait a while for the medication to clear out of their system. This can be avoided by trialling someone on the oral version and then switching to the injectable.
I hope that I haven’t confused you or totally turned you off of antipsychotics. I’ve taken quetiapine for years and will continue to take it for many more. Antipsychotics can do a world of good, and I would say the most important thing is to work with your treatment provider to find what works best for you.
I’ll close with a brief anecdote. I once had a client who had been extremely psychotic and homeless when I first started working with him. We stabilized him on risperidone, and he responded beautifully, except he was having sexual side effects. We lowered his risperidone dose and added some olanzapine, and now several years later, he’s an amazing peer leader and advocate. Meds gave this client his life back, and that’s priceless.
The rest of the Psych Meds 101 series covers:
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Ashley L. Peterson
BScPharm BSN MPN
Ashley is a former mental health nurse and pharmacist and the author of four books.