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Day # 12: Intro to Antipsychotics

Welcome back to our theme of psychotic spectrum disorders. Today we are going to start our discussion of antipsychotic medications. This is a very large topic. Today will be an introduction. We will then take a few days to discuss side effects and then wrap up the discussion with important research and clinical pearls of prescribing these medications.

Today's Content Level: Beginner


•Antipsychotic medications are a grouping of medications that have all been shown to be helpful to treat psychotic disorders as well as psychotic symptoms associated with other psychiatric and medical illnesses.

•Most antipsychotics have a number of mechanisms of action (MOA) and receptor interactions in the brain that contribute to their varied efficacy and side-effect profiles. See below for specific MOA's and target receptors.


•Chlorpromazine was synthesized in 1951 as a possible adjunct to general anesthesia. It was later discovered to have a calming effect and was later introduced into the field of psychiatry and became the first antipsychotic medication.

•Antipsychotics were initially classified according to their chemistry (phenothiaizines, butyrophenoes, diphenylbutylpiperidines, benzamides) and other fancy chemical names. This classification is rendered somewhat redundant by the broad range of chemical entities now available and by the absence of any clear structure-activity relationships for newer drugs. The chemistry of older drugs are relevant, however, as they relate to their propensity to cause movement disorders called extrapyramidal symptoms (EPS). More on EPS tomorrow.

•The first classification system for antipsychotics was divided between "Typical" and "Atypical" antipsychotics.

•The relative liability for inducing EPS was originally the primary factor behind the typical/atypical classification.

-Typical = high risk of EPS

-Atypical = less risk of EPS

•This is not a great classification system because there are a lot of medications with medium levels of risk for EPS and the affects are dose-dependent. There is also nothing either pharmacologically or chemically that clearly bind these groups together.

•Clozapine had long been known as an atypical antipsychotic on the basis of its low ability to cause EPS. Its re-marketing in 1990 signaled the beginning of a series of new medications, all of which were introduced with claim of various ‘atypicality’.

•For an interesting podcast on the history of antipsychotics check out episode 020 of the Psychiatry and Psychotherapy podcast.

New Classification: "Generations"

•Eventually a new classification system was utilized and organizes antipsychotics into "First Generation Antipsychotics (FGA)" and "Second Generation Antipsychotics (SGA)".

•All drugs introduced since 1990 are classified as SGA (i.e. all atypical).

•Classification remains problematic because neither group is defined by anything other than time of introduction which is obviously not a sophisticated pharmacological classification. Also, date of introduction is often different from date of first synthesis. For example, clozapine and olanzapine were synthesized in 1959 and 1971 respectively, but were not approved for psychiatric use until 1990.

•In all Bullet Psych materials we will use the FGA/SGA distinction out of convention more than scientific basis.

Mechanisms of action

•Psychotic symptoms have long been attributed to dysregulation in the dopamine networks within the brain. It turns out that this is an oversimplified and incomplete model of schizophrenia and other psychotic disorders, but it is a helpful model to understand how these medications work.

•All currently available antipsychotics (with the possible exception of clozapine) exert their antipsychotic effect primarily through blocking dopamine. Specifically, antagonism (or partial agonism) at post‐synaptic dopamine receptors.

•There is increasing evidence that in some patients with schizophrenia, refractory symptoms do not seem to be driven through dysfunction of dopamine pathways, and so increased dopamine blockade in such patients is of uncertain value.

•The positive symptoms of schizophrenia (hallucinations, delusions, disorganized speech, etc...) are treated by reducing dopamine in the mesolimbic dopamine pathway (nucleus accumbens, fornix, amygdala, and the hippocampus).

•The negative symptoms of schizophrenia (anhedonia, apathy, flat affect, etc.) are thought to occur due to (decreased) dopaminergic action in the mesocortical pathway (cerebral cortex). It makes sense, then, that treating with antipsychotics (blocking dopamine) can actually worsen negative symptoms in some cases.

•Most antipsychotics have a number of actions and receptor interactions in the brain that contribute to their varied efficacy and side-effect profiles. A generalization is that FGA's treat psychosis by primarily blocking dopamine (D2) receptors and that SGA's block both dopamine (D2) and serotonin (2A) receptors.

•The reality is, however, that most antipsychotics have a number of actions and receptor interactions in the brain that contribute to their varied efficacy and side-effect profiles. Notable additions include histamine, acetylcholine, and alpha-1 adrenergic.

Introduction to Clinical Use

•Both FGA and SGA antipsychotics have similar efficacies in treating the presence of positive psychotic symptoms, such as hallucinations and delusions.

SGA's (atypicals) were thought to be more effective at treating negative symptoms (such as flattened affect and social withdrawal), although this has not been consistently shown in the literature.

SGA's have largely replaced FGA's in their frequency of use due to their lower risk of causing movement disorders. However, evidence for metabolic syndrome, including weight gain, and other side effects, as well as the significant cost of these medications, means that currently both classes are used as first-line treatments.

•The choice of which specific medication to prescribe should be made based on the patient’s individual clinical presentation, past response (favorable and unfavorable), side-effect profile, and patient preference. Much more on this in a few days.

Names of Medications

•This list is not exhaustive, but is an introduction/reference to some of the most commonly used antipsychotic medications. We will discuss specific features of these medications in later lessons. Always look up dosing and side effects of a particular drug prior to prescribing.

First-Generation Antipsychotics

Divided into "potency" which means the binding affinity with the dopamine (D2) receptor. This has no correlation with effectiveness.

High Potency

Haloperidol (Haldol): PO/IM/IV/LAI.

Fluphenazine (Prolixin): PO/IM/LAI.

Mid Potency

Perphenazine (Trilafon): PO/IM.

Loxapine: PO/IM/IV.

Low Potency

Chlorpromazine (Thorazine): PO/IM/IV.

Second-Generation Antipsychotics

Asenapine (Saphris): ODT.

Clozaril (Clozapine): PO.

Iloperidone (Fanapt): PO/LAI.

Lurasidone (Latuda): PO.

Olanzapine (Zyprexa): PO/ODT/IM/LAI.

Paliperidone (Invega): PO/LAI.

Quetiapine (Seroquel): PO.

Risperidone (Risperdal): PO/ODT/LAI.

Ziprasidone (Geodon): PO/IM.

*Aripiprazole (Abilify): PO/LAI.

*Aripiprazole and related medications are technically SGAs, however sometimes called third generation due to their different mechanism of action. Instead of blocking dopamine (D2) receptors, they are partial agonists but have high binding affinity which allows less dopamine to bind to the receptors.


I hope you found this introduction helpful. Tomorrow and the next day we will discuss some of the most feared side effects of antipsychotics: extrapyramidal symptoms (EPS) and neuroleptic malignant syndrome (NMS). After that we will spend one more day on side effects and medical monitoring. Then we will round out the discussion with important research, guidelines, and clinical tips on prescribing this class of medications.

Resources for this post include:

The Maudsley Prescribing Guidelines in Psychiatry (By far my favorite psychopharmacology book, highly recommend)

Stahl's Essential Psychopharmacology Prescriber's Guide (also highly recommend as a desk reference)

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