Managing the unexpected side effects of antipsychotic treatments

By Kristen Fuller, MD | Medically reviewed by Amanda Zeglis, DO, MBA
Published September 12, 2022

Key Takeaways

  • First-generation antipsychotics have a higher likelihood of extrapyramidal symptoms (EPS), whereas second-generation antipsychotics have a higher probability of metabolic symptoms.

  • Before starting a patient on second-generation antipsychotics, assessing for any cardiac history and metabolic risks is essential.

  • If a patient develops metabolic side effects while on a second-generation antipsychotic, it should be managed in a stepwise fashion.

Antipsychotics are the first-line treatment for individuals with psychotic disorders, specifically schizophrenia; however, these medications come with potential side effects. One of the most common concerns many patients have when starting a new medicine is its potential for unwanted side effects—how will it make them feel, and what will it do to their body?

As prescribing physicians, it’s vital for us to be aware of these side effects, counsel patients on what to expect, and consider alternative options if they become too much for the patient.

Schizophrenia symptoms

Schizophrenia is a chronic mental health disorder characterized by psychotic symptoms such as hallucinations, delusions, disorganized speech, changes in personality, lack of motivation, and difficulty with cognitive tasks.[]

Schizophrenia affects less than 1% of the US population. It affects men and women equally, but often presents in men in their late teens or early 20s.

Women tend to show initial symptoms in their 20s and early 30s. Without medication, individuals with schizophrenia have an increased risk of suicide, homelessness, and substance misuse.

First- vs second-generation antipsychotics

First-generation antipsychotics are also known as typical antipsychotics or neuroleptics.[] This class includes fluphenazine, perphenazine, haloperidol, loxapine, and chlorpromazine. First-generation antipsychotics are D2 antagonists that have effects on other receptors such as muscarinic, adrenergic alpha-1, and histamine-1, giving them their side effects profile.

These antipsychotics are associated with a higher risk of EPS, which can include the inability to sit still, involuntary muscle contractions, tremors, stiff muscles, and involuntary facial movements.

As a result of these unwanted neurological side effects, second-generation (also known as atypical) antipsychotics were developed to treat schizophrenia. These include clozapine, risperidone, paliperidone, iloperidone, quetiapine, olanzapine, ziprasidone, asenapine, and lurasidone.

This class of medications also blocks D2 receptors, but what makes them different from first-generation agents is their ability to block 5HT2A receptors. As a result, this class is also known as dopamine-serotonin antagonists.

This class of medication has gained popularity due to having much lower risk for EPS than first-generation antipsychotics. However, it’s now understood that second-generation antipsychotics are more likely to produce metabolic side effects such as hyperglycemia, weight gain, and dyslipidemia. These medications are also known to have serious cardiac complications such as QT prolongation, sinus tachycardia, sudden cardiac death, myocarditis, and cardiomyopathy.[]

There is no evidence that second-generation antipsychotics are significantly more effective than first-generation antipsychotics in the treatment of schizophrenia’s cognitive and negative symptoms.

Research has shown that clozapine is the most effective antipsychotic for treatment-resistant schizophrenia.

There are newer, third-generation antipsychotics that have more recently been developed with continued efforts to minimize antipsychotic side effects profiles.

Preventing and managing side effects

Before a patient is started on a second-generation antipsychotic, it’s recommended that you take a thorough medical history to learn about their family history of sudden or premature death (at < 45 years of age), cardiac disease, diabetes, and high cholesterol.[]

Obtaining a baseline EKG, lipid panel, fasting glucose, random glucose, body mass index, and complete chemistry profile to screen for early signs of diabetes, hyperlipidemia, or a prolonged QT interval is also highly recommended before starting a patient on one of these medications.

These baseline levels should also be monitored during the use of second-generation antipsychotics. Cardiology should be consulted if there’s any evidence of heart disease, family history of cardiac disease in a first-degree relative, or if a patient develops any cardiac symptoms after being started on a second-generation antipsychotic.

Some experts recommend educating patients on healthy diet and exercise, as well as encouraging them to meet with a dietitian and make lifestyle changes.[]

Suppose an individual on a second-generation antipsychotic begins to develop metabolic side effects such as weight gain, high glucose levels, increased blood pressure, or increased cholesterol. In such cases, it’s important to manage these side effects in a stepwise fashion beginning with lifestyle modifications that include diet and exercise.

Lifestyle modifications should be continued in addition to any additional intervention.

Switching antipsychotics within the same class is another intervention to be considered. However, it is essential to balance the benefit of reducing metabolic symptoms against the risk for relapse of psychotic symptoms.

In general, clozapine and olanzapine are considered the atypical antipsychotics carrying the highest risk of weight gain, while newer atypical antipsychotics, such as risperidone and aripiprazole, are considered less susceptible to causing weight gain. Physicians need to be aware of the side effect hierarchy regarding second-generation antipsychotics in order to ensure optimal patient care.”

Diabetes should be monitored with regular HBA1c, and if pre-diabetes is suspected, then lifestyle management intervention is advised. Prescribing metformin may be considered for patients who don’t respond to strict lifestyle modifications.

For individuals who show an increase in lipid profiles that has been unresponsive to strict lifestyle interventions, a statin should be prescribed, as they are considered safe when taken with second-generation antipsychotics.

Blood pressure medication could also be added to reduce cardiovascular complications.

What this means for you

Schizophrenia is a severe chronic disorder. When left untreated, it can lead to grave complications for patients. Second-generation antipsychotics are commonly used to treat its symptoms, but come with risk of metabolic side effects. Be aware of these metabolic side effects and understand how to screen for them before initiating treatment. Know which second-generation medications have a high, moderate or low profile for metabolic side effects. If your patient develops hyperlipidemia, obesity, diabetes, or heart complications, work towards managing these concerns in order to provide optimal patient care.

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