Second-generation (Atypical) Antipsychotics

This article provides an overview of atypical antipsychotics, including the specific types, their benefits and indications, side effects, and overall treatment options.

Key Takeaways:

• Atypical antipsychotics, also known as second-generation antipsychotics, refer to the newer class of antipsychotic drugs. They primarily work by affecting dopamine and serotonin levels in the brain, which helps control psychosis and related symptoms.

• Atypical antipsychotics are most commonly used to treat schizophrenia, bipolar disorder, and severe depression. There are several other approved and off-label uses as well.

• While generally considered safer than traditional antipsychotics, second-generation antipsychotics still have several possible side effects, contraindications, and drug interactions. Thus, treatment plans are highly individualized.

Understanding Atypical Antipsychotics

Atypical antipsychotics are also referred to as second-generation antipsychotics. They are used to treat schizophrenia, bipolar mania, psychosis, and several other mental health conditions. Compared to first-generation (typical) antipsychotics, atypical antipsychotics are often the preferred medication for psychotic episodes, given their safer side effect profile and enhanced clinical benefits. ^{[1] [2]}

How do Atypical Antipsychotics Work?

Atypical antipsychotics work through several mechanisms in the brain. The majority of atypical antipsychotics work by blocking dopamine and serotonin receptors. The effect on dopamine is beneficial since excessive dopamine activity is linked to hallucinations, delusions, and other aspects of psychosis, while the effect on serotonin can help improve mood and control overexcitation in the brain. ^{[1] [3]}

Atypical antipsychotics may also affect acetylcholine, adrenaline, and other neurotransmitters, depending on the specific drug involved. ^[1]

Atypical vs Typical Antipsychotics

Typical antipsychotics are also known as first-generation antipsychotics, and were developed as early as the 1950s. Atypical antipsychotics were developed later, starting in the 1960s.

Typical antipsychotics primarily inhibit the effects of dopamine, while atypical antipsychotics affect both dopamine and serotonin. There are nuances within each drug’s effects, but these are the overarching patterns. ^[3]

Today, atypical antipsychotics are the preferred treatment for psychoses and several other mental health conditions. One of the main reasons for this is their decreased likelihood of causing extrapyramidal side effects, which are various movement disorder symptoms, such as tremors, muscle spasms, and restlessness. Furthermore, atypical antipsychotics have a more favorable clinical profile. ^{[1] [4]}

Types of Atypical Antipsychotics

There are several FDA-approved atypical antipsychotics. This includes:

• Amisulpride (Solian®)

• Aripiprazole (Abilify®, Aristada®)

• Asenapine (Secuado®, Saphris®)

• Brexpiprazole (Rexulti®)

• Cariprazine (Vraylar®)

• Clozapine (Clozaril®, Versacloz®)

• Iloperidone (Fanapt®)

• Lumateperone (Caplyta®)

• Lurasidone (Latuda®)

• Olanzapine (Zyprexa®, Lybalvi®, Symbyax®)

• Paliperidone (Invega®)

• Pimavanserin (Nuplazid®)

• Quetiapine (Seroquel®)

• Risperidone (Risperdal®, Peseris®)

• Ziprasidone (Geodon®)

Atypical antipsychotics come in several different forms, including conventional oral tablets, capsules, or liquid, as well as immediate-release injectables, long-acting injectables, and orally disintegrating tablets. ^[1]

Oral dosing is the most common and preferred by most patients. In these cases, the medications are taken once daily, sometimes twice per day. Immediate-release injectables are used primarily for emergencies requiring extreme agitation or acute psychosis. Longer-acting injectables are taken every 2 to 4 weeks. ^{[1] [5]}

What Conditions do They Treat?

Atypical antipsychotics are approved to treat several mental health conditions, including:

• Schizophrenia.

• Bipolar I disorder (BP-I).

• Irritability in autism spectrum disorder (ASD).

• Major depressive disorder (MDD).

• Treatment-resistant MDD.

• Acute agitation within BP-I and schizophrenia.

• Schizoaffective disorder.

• Psychosis associated with Parkinson’s disease.

• Tourette disorder.

Importantly, not all atypical antipsychotics are approved for all of these conditions. Most individual medications are approved for 1 to 3 conditions, most commonly BP-I and schizophrenia. Aripiprazole is the most diverse, with a total of 5 approved indications. ^[1]

Antipsychotics are also used off-label in certain instances, such as for:

• Eating disorders.

• Personality disorders (such as borderline personality disorder).

• Post-traumatic stress disorder (PTSD).

• Obsessive-compulsive disorder (OCD).

• Anxiety.

• Dementia in elderly patients.

• Substance use disorders.

• Attention-deficit hyperactivity disorder (ADHD).

Effects of Atypical Antipsychotics

Atypical antipsychotics have several possible beneficial effects. Within the context of schizophrenia, atypical antipsychotics can reduce symptoms of psychosis, such as auditory or visual hallucinations, delusions, and paranoia. ^{[1] [3] [6]}

Atypical antipsychotics can also help individuals think more clearly and logically. They also help control agitation and irritability, and promote a more balanced mood. This is particularly helpful for individuals with BP-I, as well as ASD, and certain behavioral disorders. ^{[1] [6]}

Furthermore, atypical antipsychotics can improve mood and reduce depressive symptoms. They are particularly relevant in cases of severe or treatment-resistant depression. ^[6]

As a result, these effects can help individuals function better and experience improved mental well-being, including in cases where this would otherwise be nearly impossible.

Adverse Effects of Atypical Antipsychotics

Atypical antipsychotics are considered safer overall compared to typical antipsychotics, but they still have several possible adverse effects. Your doctor will work with you to figure out the most effective and safest medication for your needs and situation.

Common side effects of atypical antipsychotics include:^[1][2][3]

• Weight gain

• Metabolic syndrome, which involves 3 or more of the following:

• Excess abdominal fat.

• High triglycerides.

• High blood pressure.

• High blood sugar.

• Low HDL cholesterol.

• Increased appetite.

• Diabetes.

• Drowsiness.

• Anxiety.

• Sun sensitivity.

• Temperature sensitivity.

• QTc prolongation (a heart rhythm abnormality).

• Sexual dysfunction (such as decreased libido).

Less common side effects include: ^{[1] [3]}

• Myocarditis (inflammation of the heart muscle).

• Suicidal thoughts.

• Extrapyramidal side effects:

• Involuntary body movements.

• Muscle stiffness.

• Restlessness.

• Tremors.

• Rash.

• Hives.

• Seizures.

• Agranulocytosis (decreased granulocytes, a type of white blood cell).

Who Shouldn’t Take Atypical Antipsychotics?

Atypical antipsychotics are contraindicated for people with tardive dyskinesia, Parkinsonism, and a history of neuroleptic malignant syndrome, as they may worsen these conditions (although the risk is lower with atypical versus typical antipsychotics). There is also an increased risk of death in older individuals with dementia when using atypical antipsychotics. ^[1]

Antipsychotics are also not recommended for pregnant or breastfeeding women, especially during the first trimester of pregnancy. They are only used if a thorough evaluation deems that the benefits are greater than the risks. ^[3]

In addition, atypical antipsychotics are not recommended in most cases of delirium, although they may be used in severe instances. ^[1]

Other contraindications with atypical antipsychotics include: ^[1]

• Tay-Sachs disease.

• Glaucoma.

• Severe liver disease.

• Severe neutropenia.

• Bone marrow depression.

Dangerous Drug Combinations

Many atypical antipsychotics either induce or inhibit enzymes involved in drug metabolism. This is important because this can cause interactions when combined with other drugs that exert similar effects, leading to increased or decreased drug levels in the body, depending on both drugs’ effects.

Common classes of drugs that may interact with atypical antipsychotics include: ^{[1] [6]}

• Antidepressants (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline).

• Also includes the over-the-counter supplement, St. John’s wort.

• Anticonvulsants (e.g., carbamazepine, phenytoin).

• Anti-infective agents (e.g., ketoconazole, clarithromycin, voriconazole).

Certain atypical antipsychotics may also be dangerous when combined with alcohol or tobacco consumption. ^[1]

How Long Does Antipsychotic Medication Treatment Last?

The length of antipsychotic treatment depends on several factors, such as the specific condition, treatment response, and symptom severity. Most people with more serious symptoms or conditions, such as schizophrenia and BP-I, will be prescribed antipsychotic medication long-term. This is to help these individuals stay symptom-free and reduce the risk of worsening or returning symptoms.

In other cases, such as acute instances of agitation or psychosis, antipsychotic medications may be administered for short-term, such as a few days to weeks.

Typically, when starting a new antipsychotic medication, it is administered for at least a month before analyzing the benefits, effects, and overall utility.

Final Thought

Atypical antipsychotics are potentially valuable medications for the treatment of schizophrenia, bipolar disorder, severe depression, and other mental health conditions. They are generally recognized as safer and more effective than older antipsychotics, but there are still possible side effects and drug interactions. Talking with your doctor is essential to determine the safest and most appropriate antipsychotic medication for your needs and circumstances.