Antipsychotics are some of the most common medications used by psychiatrists. Despite their title of “antipsychotics,” they are actually used for a wide variety of symptoms. Besides their use for psychotic disorders such as schizophrenia, some are also used as single agents or in combination with mood stabilizers for bipolar disorder, or to augment antidepressants for depression. Some are commonly used for off-label purposes; a practice I try to avoid when possible. The standard medication dosages vary depending on the targeted illness. In this article, I will specifically focus on using antipsychotics for the treatment of schizophrenia, and therefore the dosages listed here are for that indication only unless stated otherwise.

Antipsychotics have more similarities than differences. They all modulate the dopaminergic system to some degree. The atypicals also modulate the serotonergic system, and are thus differentiated from the typical antipsychotics. At first glance, knowing which to choose can seem like choosing one snow flake in a snowstorm. However, there are clear differences that should be kept in mind when deciding. By understanding the common and rare side-effects of each medication, the available formulations, and by taking the patient’s history and preferences into account, we can usually pick a couple superior choices out of the medley.

To understand the side-effects of a medication, we can study which receptors the medication binds and at what affinity. The following table links receptor binding and clinical presentation:

Receptors Effects
D2 family (D2, D3, D4)
  • Positive symptoms of schizophrenia
  • Extrapyramidal symptoms (EPS)
  • Akathesia
  • Tremors
  • Hyperprolactinemia and gynecomastia
5-HT2A/2C
  • Negative symptoms of schizophrenia
  • Decrease likelihood of EPS
  • Weight gain
α1-adrenergic
  • Orthostatic hypotension
  • Dizziness
  • Sedation
M1-muscarinic
  • Sedation
  • Dry mouth
  • Constipation
  • Blurred vision
H1-histaminic
  • Weight gain
  • Sedation

As shown above, medications that potently block D2 receptors are expected to cause more EPS. If they act on 5HT2A/2C receptors, they may work better for the negative symptoms of schizophrenia and reduce risk for EPS, but may also cause more weight gain. Acting on histaminic receptors will cause sedation and weight gain.

In addition to understanding the side-effects, knowing which formulations of the medications are available can help guide our decision. For example, some medications come as a liquid or as a rapidly dissolving tablet. Therefore, if we are worried that the patient may try to hide the medication in their mouth and spit it away as soon as the nurse shifts his/her gaze, we may want to consider these “non-cheekable” formulations. Remember to suspect cheeking if the patient is not improving or is not showing expected side-effects even on high doses of the medication. Other formulations include injectables, which can be given IM (intramuscularly) when a patient refuses to take the medications PO (by mouth) even after they were “Riese’d” (This term is specific to California and means that the hospital was given permission by the court to administer the medication regardless of patient’s willingness to accept it).  Some medications also come in a long-acting injectable formulation that can be injected at regular intervals (q [every] 2 weeks, q month, etc.). These can be useful for patients with history of noncompliance with oral medications, or for homeless patients who may have difficulty storing or taking a medication daily. Also, many patients may prefer only having to worry about taking medications once a month instead of twice daily. Finally, some medications are much more expensive than others. All things being equal, choose generic.

Some side-effects are common to most antipsychotics. One such example is prolonged QTc with the possibility of arrhythmia. Checking an EKG before starting an antipsychotic for baseline QTc interval is wise. QTc intervals between 450-500ms are worrying, and intervals above 500ms are very worrying. Also, all antipsychotics can cause NMS (neuroleptic malignant syndrome), a potentially lethal side-effect! If you suspect NMS (rigidity, fever, altered mental status, diaphoresis, unstable vital signs), immediately discontinue all antipsychotic meds. Do not taper down gradually and do not give another dose for acute agitation. Just discontinue immediately! Get labs (CPK) to confirm and transfer to ICU. Education saves lives =)

Keep in mind the Black Box Warning on antipsychotics: patient with dementia that are on antipsychotics are at higher risk for death, mostly due to heart disease or infections.

As always, I cannot guarantee the accuracy of the information found in this article (of course, if you notice any inaccuracies, make sure to post in the comments!). Please be aware that the doses provided are the doses that I typically use for an average adult patient with normal liver functions, normal kidney functions, and normal and stable vital signs.

To familiarize you with the most commonly used antipsychotics, I will give a brief overview for each:

Risperidone (Risperdal)

Binding Affinity Profile
D2 5-HT2A α1 M1 H1
3 4 3 0 1
4=very high; 3=high; 2=moderate; 1=low; 0=negligible

Description: This atypical antipsychotic has strong affinity to D2. Thus, expect high frequency of EPS which can usually be alleviated with benztropine or diphenhydramine. The strong affinity to 5HT2A receptors means you can expect weight-gain. Risperidone comes in a dissolvable formulation as a melting tablet called Risperidal m-tab. There is no rapid-acting injectable and therefore it cannot be injected for acute agitation. However, there is a long acting injectable that is given q2weeks,

When to choose: Patients tend to tolerate risperidone well. It’s not very sedating and can be titrated up quite rapidly to the target dose. The long-acting formulation of risperidone, Risperdal Consta, can be used in willing patients when compliance to PO medications may be problematic. Dose of Risperidone Consta ranges from 25mg to 50mg IM q2weeks.

When not to choose: Risperidone can cause increased weight and metabolic syndrome, so be careful when prescribing for a high-risk individual. It can also cause permanent gynecomastia in men because of the release of dopamine inhibition of prolactin in the pituitary gland. In addition, keep in mind that there is no instant-release IM formulation (i.e., we cannot write Risperidone 2mg IM stat), which can be a problem for a patient who refuses to take the medication and needs to be Riese’d. Sometimes we can write “give risperidone m-tab 2mg PO BID, if refused give haloperidol 5mg IM for each dose refused.” However, this is not ideal since the patient may then end up getting two antipsychotics at sub-therapeutic doses.

How to dose: In an inpatient setting, start 1-2mg PO BID and titrate up by 2mg per day distributed BID. Target dose is 6-8mg total daily, with approved maximum of 16mg (I have never actually seen anyone getting this much!) Example: Day 1: 1mg BID. Day 2: 2mg BID. Day 3: 3mg BID. Usually if I start day 1 with 2mg BID, I will add benztropine 0.5-1mg PO BID prophylactically for EPS.

Paliperidone (Invega)

Binding Affinity Profile
D2 5-HT2A α1 M1 H1
3 4 3 0 1
4=very high; 3=high; 2=moderate; 1=low; 0=negligible

Description: Paliperidone is the active metabolite of risperidone and has very similar binding affinities. The capsule of Invega is high-tech and works by releasing the active ingredient out of the indigestible capsule through osmosis. The patient will sometimes see the capsule come out empty in the stool. Paliperidone is approved for schizophrenia as well as schizoaffective disorder. Theoretically, given that it is risperidone’s active metabolite, its plasma level is less determined by liver function. Like risperidone, paliperidone does not have an instant-release injectable formulation, but has a long-acting injectable called Invega Sustenna that can be injected qmonth. To give the long-acting injection, make sure that the patient does not have adverse effects to PO formulation such as an allergic reaction or severe EPS. Remember that once you inject a long acting medication, only time will take it out. At OVMC, we do not carry the capsule formulation of paliperidone, but we do carry Invega Sustenna.

When to choose: When liver function is impaired, probably choose paliperidone over risperidone. Also, when chronic noncompliance is an issue, the long-acting injectables may be a better choice than PO meds.

When not to choose: Like risperidone, paliperidone can cause weight-gain and metabolic syndrome. It can also cause gynecomastia. There is no instant-release IM formulation. Currently, PO paliperidone is a much more expensive alternative to the now generic risperidone, but the cost of Invega Sustenna is comparable to Risperdal Consta (at least, that’s what the pharm reps tell me).

How to dose: Start paliperiodone at 6mg PO daily, and quickly increase to target dose of 6-12mg (9mg is common). Paliperidone is usually given once daily. After a short trial of adequate dose of PO risperidone or paliperidone (about 6mg total daily of risperidone or 9mg total of paliperidone), you can instantly discontinue the PO meds and give Invega Sustenna 234mg IM x1. In 4 to 12 days, you give a second loading dose of Invega Sustenna 156mg IM x1. After that, give Invega Sustenna 117mg IM qmonth (these are standard doses although the exact doses should be individualized). Just make sure that the patient actually received the injection prior to discontinuing the oral dose (otherwise the patient may be without meds for the day!)

Aripiprazole (Abilify)

Binding Affinity Profile
D2 5-HT2A α1 M1 H1
3* 3 2 0 2
* partial agonist; see text
4=very high; 3=high; 2=moderate; 1=low; 0=negligible

Description: What sets aripiprazole apart is that it’s a partial dopamine agonist. Because it’s only a partial agonist, it has the net effect of decreasing receptor activity where dopamine is abundant while simultaneously increasing receptor activity where dopamine is scarce. This unique mechanism of action means that EPS is an uncommon side-effect, but akathesia occurs in about 10% of treated patients. Akathesia is basically a very uncomfortable restlessness. The patients sometimes reports a feeling of “crawling out of my skin” and they cannot sit still during the interview. Akathesia is usually treated with propranolol (if blood pressure and HR are not too low). Aripiprazole is less sedating than many of the other antipsychotics (although it still can be sedating). Aripiprazole at lower doses can be used for major depressive disorder, but only to augment an antidepressant such as SSRIs. Aripirazole has a melting formulation called Abilify Discmelt (unavailable at OVMC) and a long-acting injectable called Abilify Maintena (also unavailable at OVMC). Abilify Maintena is usually dosed at 300mg to 400mg IM qmonth. There is no instant-release injection.

When to choose: Aripirazole’s major achievement is that it is far less likely to cause extreme weight-gain or metabolic syndrome. Therefore, consider it for obese patients or for patients with diabetes. It is also less sedating compared to many other antipsychotics, and therefore some higher-functioning patients prefer it.

When not to choose: The lack of sedation can be an asset in an outpatient setting, but for acutely dangerous patients in an inpatient setting some sedation can be helpful. If akathesia develops and is not alleviated with propranolol (or if propranolol is not an option), consider decreasing the dose or switching to another antipsychotic.

How to dose: For schizophrenia, start at 10-15mg once daily and increase by 5-10mg daily to a max approved dose of 30mg. For augmenting an antidepressant for major depressive disorder, start at 5mg and go up to 10-15mg (usually in 2-5mg increments daily).

Olanzapine (Zyprexa)

Binding Affinity Profile
D2 5-HT2A α1 M1 H1
2 3 2 3 3
4=very high; 3=high; 2=moderate; 1=low; 0=negligible

Description: Olanzapine can cause severe obesity, metabolic syndrome, sedation, and EPS. So why is it used so often? Because studies have shown it to be more effective than other antipsychotics with the exception of clozapine. It also comes in a wide array of formulations, including a short acting injectable (which should never be combined with a benzodiazepine IM because of reported cases of death by respiratory depression). There is also a dissolving formulation called Zyprexa Zydis and a long-acting injectable called Zyprexa Relprevv (not available at OVMC). The maximum recommended dose for Zyprexa Relprevv is either 300mg po q2weeks or 405mg po q4weeks.

When to choose: Olanzapine is effective for very agitated patients because of its sedating effects. It may also be slightly more effective than most other antipsychotics. It is very easy to dose and is convenient given its various formulations.

When not to choose: Obviously, try to avoid prescribing for obese or diabetic patients. Avoid if weight-gain is a major concern for the patient.

How to dose: Olanzapine can be titrated up relatively quickly in an inpatient setting. Start with 10mg daily (usually qhs) and titrate up to 20mg po qhs. While the dose can be given once daily, it can be split to BID if needed to minimize side-effects. It is common in an inpatient setting to give doses above 20mg, but antipsychotic effect benefit may be minimal beyond even 10mg if we believe the studies (and we do… Because science). Exceptions occur, however, for example in patients who only partially respond to 20mg or who are extremely agitated and acutely violent. Anyway, mega-doses of olanzapine are usually temporary, and will be tapered down for maintenance dose.

Quetiapine (Seroquel)

Binding Affinity Profile
D2 5-HT2A α1 M1 H1
1 1 2 2 3
4=very high; 3=high; 2=moderate; 1=low; 0=negligible

Description: Quetiapine, like olanzapine, can cause obesity, metabolic syndrome, and sedation. However, given its low D2-binding affinity, it is far less likely to cause EPS. Quetiapine can also cause orthostatic hypotension and should be used very cautiously if the patient is at risk for fall or has a low baseline blood pressure. Patients on quetiapine most commonly complain of dry mouth, dizziness, and sedation. Unfortunately, there is no dissolving tablet or an injectable, and therefore you may want to reconsider its use when cheeking is suspected. There is a Seroquel XR formulation for once daily dosing, but unfortunately it’s not stocked at OVMC. Aside from treating schizophrenia, quetiapine is approved for augmenting an antidepressant (usually SSRI) for major depressive disorder. During your career, you will frequently encounter physicians using low doses of quetiapine (25-100mg) to treat a vast array of problems–from anxiety to insomnia. In my opinion, there are far better medications to use for anxiety and insomnia that do not involve possibly developing diabetes and other complications.

When to choose: Quetiapine is quite sedating and therefore can be very useful in patients who cannot sleep or who are very hyper/agitated. Also, in patients where EPS is a major concern, quetiapine is a good choice. Thanks to its low D2 affinity, quetiapine is a common choice for patients with Parkinson’s who develop psychosis.

When not to choose: Keep in mind that some people abuse quetiapine, and that there is a street value for quetiapine. Therefore some patients may ask for it specifically so that they can sell it or mix it with other drugs. In fact, many prisons banned quetiapine use. The street name for quetiapine combined with cocaine is “Q-ball”, “quell”, “snoozeberries”, and “Susie-Q”. Other combinations include quetiapine and opiates which can cause increased QT prolongation. Also, keep in mind that quetiapine can give a false positive for methadone on urine tox.

How to dose: It is usually dosed twice daily, with the therapeutic dose ranging from 600mg to 800mg. In an inpatient setting with very closely monitored patients with schizophrenia, I usually start with a dose of  200mg po qhs and titrate up by a total of 200mg daily until target dose. Example: Day 1: 200mg qhs. Day 2: 200mg bid. Day 3: 300mg bid. Day 4: 400mg bid. Doses for augmenting an antidepressant is maxed at 300mg (for Seroquel XR).

Coming soon:

Ziprasidone (Geodon)

Lurasidone (Latuda)

Haloperidol (Haldol)

Chlorpromazine (Thorazine)

Clozapine

Antipsychotics: How to Choose

Omer Liran


Omer Liran is an attending inpatient psychiatrist at Olive View-UCLA Medical Center and an Assistant Clinical Professor at David Geffen School of Medicine at UCLA.


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