Image: Typical vs. Atypical Antipsychotics

The development of antipsychotics is often seen as one of the most remarkable advances in the medical field. Formerly referred to as major tranquilizers or neuroleptics, antipsychotic medications are generally used to treat psychotic disorders.

Almost 70 years ago, the first typical antipsychotics were developed. However, doctors during this time only had few choices of medication for patients. As a result, these patients had to suffer from movement disorders, which is a common side effect in typical antipsychotics.

Years later, the development of a newer class of drugs known as atypical antipsychotics was seen as a game-changer in the field. Mainly because these medications showed a lower risk of drug-induced movement disorders than their predecessors had. But that’s not to say they didn’t come with side effects.

Aside from their history, however, what else is worth knowing about antipsychotics? Read on to learn more about the most important information you should know about this group of drugs, including:

  1. The differences between typical and atypical antipsychotics
  2. How they work
  3. Medications under each type of drug
  4. Mild and serious side effects
  5. Their black box warning
  6. Which is more effective

Typical & Atypical Antipsychotic Agents: By Definition

Typical antipsychotics were developed in the early 1950s. And since they first existed before their counterpart, they are also called first-generation antipsychotics (FGAs).

Sometimes also referred to as conventional antipsychotics, examples of some best known typical antipsychotics were Haldol (haloperidol) and Thorazine (chlorpromazine).

And although this class of antipsychotics is effective in the treatment of psychosis and positive symptoms of schizophrenia, a major drawback of these drugs is that they are associated with a wide array of side effects. Some of which can be severe.

These side effects include extrapyramidal symptoms or drug-induced movement disorders and tardive dyskinesia. The term “neuroleptic” was used to describe these side effects and therefore was closely associated with typical antipsychotics.

Neuroleptic means these drugs can cause neurolepsis, a syndrome that has three main features:

  • Psychomotor slowing
  • Emotional quieting
  • Affective indifference

For many years, however, physicians believed that this syndrome was a prerequisite for any drug to be effective against schizophrenia. Later on, it became clear that these symptoms do not indicate the effectiveness of a drug and these effects also lead to patients’ non-compliance with medication.

On the other hand, atypical antipsychotics are a newer class of drugs that are also called second-generation antipsychotics (SGAs). The main difference from its counterpart is that it has a much lower risk of extrapyramidal symptoms such as tardive dyskinesia.

The first atypical antipsychotic drug was clozapine. When clozapine was discovered, it became evident that this drug can apparently improve delusions and hallucinations in treatment-resistant patients. In other words, it is believed that atypical antipsychotics have more clinical advantages compared to typical antipsychotics.

However, at present, the more negative effects of atypical antipsychotics have been coming to light — particularly with risperidone. Risperidone is an atypical antipsychotic medication also sold under the brand name Risperdal. Originally prescribed to treat schizophrenia and the manic symptoms of bipolar disorder, the drug was found to have obvious risks of male breast growth and an increased risk of death among elderly patients with dementia.

Despite being aware of these risks, however, the manufacturer of Risperdal still aggressively marketed the drug to older people and children. This ultimately gave rise to several Risperdal lawsuits being filed all over the United States. To date, Johnson & Johnson already paid billions of dollars in settlements awarded in damages to victims who developed gynecomastia or male breast growth.

Furthermore, the clinical antipsychotic trials of intervention effectiveness (CATIE) also found that in spite of patients’ high tolerability to atypical antipsychotics, at present, there is a high dropout rate in the use of these drugs due to either inefficacy or intolerable side effects.

FGAs vs. SGAs: How do they work?

With regards to their mechanism of action, these drugs have certain differences, but also some degree of similarity.


In the late 1950s, dopamine was discovered and recognized as a type of neurotransmitter. Sometimes called a chemical messenger because it is used by our nervous system to send messages between neurons, dopamine also plays a role in allowing us to feel pleasure and an even bigger role in our brain’s reward system.

To some degree, both first and second-generation antipsychotics are D2 antagonists. This means that they both reduce dopaminergic neurotransmission by blocking a particular subtype of the dopamine receptor called the D2 receptor.

And why does this dopamine receptor need blocking?

This is because, in schizophrenia, dopamine is associated with hallucinations and delusions. Basically, areas of the brain that run on dopamine may become overactive, and antipsychotic drugs work by stopping this hyperactivity.


Aside from D2 antagonism, FGAs can also block other receptors such as muscarinic, adrenergic alpha 1, and histamine-1. However, this ability to have an effect on these receptors also contributes to their side effects profile.

On the other hand, SGAs are also known for blocking D2 receptors. But what makes them different from SGAs is their ability to block serotonin receptors known as 5HT2A receptors. This known 5HT2A antagonism in SGAs also contributes to their lower risk of extrapyramidal symptoms.

Most Commonly Used Antipsychotic Medications

Some of the most commonly prescribed typical or first-generation antipsychotics include:

  • Haldol (haloperidol)
  • Thorazine (chlorpromazine)
  • Loxitane (loxapine)
  • Moban (molindone)
  • Mellaril (thioridazine)
  • Serentil (mesoridazine)
  • Navane (thiothixene)
  • Trilafon (perphenazine)

On the other hand, the following are atypical or second-generation antipsychotics:

  • Clozaril (clozapine)
  • Risperdal (risperidone)
  • Geodon (ziprasidone)
  • Seroquel (quetiapine)
  • Invega (paliperidone)
  • Zeldox (ziprasidone)
  • Zyprexa (olanzapine)
  • Abilify (aripiprazole)

Side Effects from Taking Antipsychotics

With regards to the adverse effects of the two types of antipsychotics, although typical antipsychotics are linked to a higher risk of neurological side effects, this risk is also present in atypical antipsychotics. The only difference is that in the latter, there is a much lower risk of these side effects.

With that said, in general, people who take antipsychotic medications may experience the following side effects:

  • Extrapyramidal Side Effects. Extrapyramidal effects are commonly caused by antipsychotic medications. Extrapyramidal symptoms may include tardive dyskinesia, dystonic reactions, acute dyskinesias, akathisia, Parkinsonism, and neuroleptic malignant syndrome.
  • Cardiovascular Adverse Effects. Antipsychotic drugs can also cause various cardiovascular complications, including hypertension, arrhythmias, angina, chest pain, myocarditis, phlebitis, and orthostatic hypotension.
  • Metabolic Adverse Effects. Antipsychotics are also linked to varying degrees of gastrointestinal effects, including weight gain, dry mouth, constipation, impaired glucose metabolism, heartburn, dyspepsia, abdominal cramps, and dyslipidemia.
  • Reproductive Effects. Another side effect of treatment with these medications is its known disruption of reproductive function. Side effects may include ejaculatory dysfunction, impotence, testicular swelling, increased or decreased libido, breast engorgement, vaginal itching, and galactorrhea.

Antipsychotics Have a Black Box Warning

All antipsychotics — typical or atypical — come with a black box warning. A black box warning is the most serious warning that the U.S. Food and Drug Administration (FDA) issues to certain medications.

This FDA warning aims to alert healthcare providers or patients about potentially serious or life-threatening adverse effects of a drug.

In the case of antipsychotics, this group of medications earned a black box warning because they are linked to increased rates of stroke and death in elderly patients with dementia.

Despite their obvious and well-documented risks, however, antipsychotics are still widely used today. One main reason is that there is only a limited number of medications that can treat psychiatric conditions like psychosis and agitation in dementia.

If you have a loved one who has been prescribed with antipsychotic medications, their doctor may consider whether the supposed benefits of taking these medications outweigh the risks.

Is one more effective than the other?

There is an ongoing debate among experts whether newer atypical antipsychotics are more effective than typical or conventional antipsychotics.

And while at first glance, SGAs may seem to be preferable to FGAs, the effectiveness of the latter over the former has not been adequately established yet.

In fact:

There are two important clinical trials that helped shed some light on this controversy. The first one is funded by the National Institutes of Mental Health called the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). The other one is funded by the United Kingdom’s National Health Service (NHS), the Cost Utility of The Latest Antipsychotics in Severe Schizophrenia.

Findings from these trials showed that:

  • There is no evidence of the benefit of atypical over typical antipsychotics in the treatment of negative symptoms of schizophrenia.
  • Clozapine was found to be the most effective drug for patients with poor symptom response to previous antipsychotic medication trials, but it was also linked to some adverse effects.
  • There is a high discontinuation rate with atypical agents because of either inefficacy or intolerable side effects.

The Takeaway

Both typical or conventional and atypical antipsychotics work as D2 antagonists. However, typical antipsychotic agents are linked to a higher risk of movement disorders called extrapyramidal side effects.

On the other hand, a key feature of atypical agents is that they also work as a 5HT2A antagonist, which contributes to their lower risk of extrapyramidal effects. However, they are linked to a higher risk of metabolic side effects.

Finally, although there is an ongoing controversy on which of the two is more effective, two clinical trials found that there is no evidence that atypical antipsychotics are better than typical antipsychotic drugs when it comes to treating the cognitive and negative symptoms of schizophrenia.

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