What is Neuroleptic Agent Toxicity?
Neuroleptic agents, also known as ‘antipsychotics,’ are a wide range of medicines initially designed to treat psychosis – a severe mental disorder triggered by various mental health and physical conditions. Over the last 20 years, doctors have also started using these medicines to treat non-psychiatric conditions, such as nausea and vomiting, dizziness, headaches, Tourette syndrome (a nervous system disorder involving unwanted sounds and tics), and post-herpetic neuralgia (nerve pain following shingles).
There are two major types of antipsychotics based on their properties and side effects: ‘typical’ antipsychotics, also known as first-generation antipsychotics (FGAs), and ‘atypical’ antipsychotics, or second-generation antipsychotics (SGAs). The SGAs, a more modern version, have largely taken over the role of FGAs in treating primary psychosis, but FGAs are still commonly used in non-psychiatric treatments.
However, like many other medications, neuroleptics can have various side effects, ranging from minor inconveniences to severe, life-threatening risks. As these drugs become more commonly used, it’s crucial for everyone involved – from medical providers to patients – to understand these potential risks. This understanding will aid doctors in preventing and dealing with these side effects and will help them guide and counsel patients effectively.
The following provides a brief overview of the most common and serious side effects associated with antipsychotic medications. It’s important to note that each antipsychotic medication can have different side effects and risks. This article provides a general understanding of the potential issues with antipsychotic treatments as a whole, rather than an exhaustive review of each individual drug.
What Causes Neuroleptic Agent Toxicity?
While different types of antipsychotic medications can help manage psychosis, their safety and potential side effects can vary. Notably, a drug called clozapine is especially effective for treatment-resistant schizophrenia, a condition where other medications don’t work. However, the side effects can be different between individual medications and between two groups of drugs: first and second-generation antipsychotics.
First-generation antipsychotics can often lead to side effects like muscle stiffness, abnormal movements (extrapyramidal symptoms), involuntarily facial and body movements (tardive dyskinesia), increase in a hormone called prolactin (hyperprolactinemia), a rare but serious condition called neuroleptic malignant syndrome that affects the nervous system, and longer heartbeats (QT interval prolongation).
On the other hand, common side effects with second-generation antipsychotics can include weight gain and associated metabolic issues, low blood pressure (hypotension), sleepiness (sedation), and dry mouth, blurred vision, or problems urinating (anticholinergic symptoms). It’s also important to note that using second-generation antipsychotics to manage psychiatric symptoms in people with dementia has been found to increase the risk of death.
Risk Factors and Frequency for Neuroleptic Agent Toxicity
In the United States every year, about 5,800 adults receive treatment in emergency rooms due to harmful effects from First Generation Antipsychotics (FGAs). This equals to 26 emergency room visits for every 10,000 prescription outpatient visits. Patients may need this treatment due to unintentional overdoses, intentional overdoses, and other negative effects not related to overdoses.
Haloperidol, a common FGA, is often the cause of these emergency room visits more than any other antipsychotic medication. Around 20% to 35% of patients who use these medications might experience harmful side effects. Those who are more likely to develop these side effects include individuals taking higher doses, high-potency agents, females, older adults, people with cognitive issues and those infected with HIV.
Second Generation Antipsychotics (SGAs) also have high toxicity issues. For example, in 2009, poison control centers in the United States received more than 43,000 calls about people exposed to unusual antipsychotics. Similarly, in 2010, the California Poison Control System received over 4,000 calls regarding exposures to antipsychotics. Two thirds of these calls were about intentional ingestions, and more than 90% involved atypical antipsychotics.
Signs and Symptoms of Neuroleptic Agent Toxicity
Extrapyramidal Symptoms (EPS) can show a wide range of signs. These may include sudden, abnormal movements and stiff muscles, slowed movements, inability to move, and a feeling of restlessness. Most of the time, these signs show within hours to weeks after starting a medication or when there is a dosage increase.
On the other hand, Tardive Dyskinesia (TD) shows itself as involuntary movements of various body parts, such as the mouth, tongue, face, limbs, or trunk. Common symptoms include lip-smacking, abnormal tongue or jaw movements, facial grimacing, and uncontrolled movements in the trunk or limbs. The risk of developing Tardive Dyskinesia increases with age, how long a person has been exposed to certain medications, and previous occurrences of EPS. Although the onset of TD is usually delayed, not appearing until after three months of medication use and most commonly occurring after one to two years. The symptoms of TD can vary in intensity but they can be stigmatizing, and in some cases disfiguring, for the patients who experience them. This condition has a cumulative risk of about 5% per year with the use of all first-generation neuroleptics. This increased risk led to the replacement of first-generation medications with second-generation ones for treating chronic mental health conditions.
Telling the difference between EPS and Tardive Dyskinesia can be difficult. However, the time from when the medication is started to when symptoms occur can sometimes help. This is crucial because symptoms of EPS will go away once the problematic medication is stopped, while TD is usually progressive and irreversible. Lastly, the most life-threatening side effect of neuroleptic use is Neuroleptic Malignant Syndrome (NMS). NMS is characterized by confused mind, instability of the automatic nervous system that controls vital body functions, high body temperature, and characteristic “lead pipe” muscle rigidity. NMS usually occurs within the first two weeks of starting a medication. However, it can occur after a single dose or after years of treatment. Excessive sweating is more common in NMS caused by second-generation antipsychotics (SGAs), while rigid muscles, shaking, and fever are seen less commonly than in cases caused by first-generation antipsychotics (FGAs).
Testing for Neuroleptic Agent Toxicity
The process of diagnosing toxicity from medication(s) targeting your nervous system is primarily based on a detailed discussion with you about your symptoms, medical history, and a physical examination by your doctor. This is crucial because there are no lab tests or imaging techniques that can confirm this type of toxicity. Lab tests and other investigations may still take place, but their main purpose is to rule out other conditions that may cause similar symptoms.
Your doctor will want to know about any medications you’re taking, recent changes in dosage, and the timing of symptoms in relation to when you started taking your medication. They will also want to understand how your symptoms have developed over time.
Treatment Options for Neuroleptic Agent Toxicity
If you experience Extrapyramidal symptoms (EPS) – side effects that can cause movement disorders or muscle problems – as a result of certain antipsychotic medications, the best treatment is usually to stop taking the problematic medication. However, if you have an urgent muscle spasm or unusual body positions (known as an acute dystonic reaction), doctors may prescribe drugs such as benztropine or diphenhydramine, which are termed anticholinergic medications, to relieve your symptoms. Note that these medications can actually worsen another condition called tardive dyskinesia (TD), which refers to involuntary, repetitive body movements. Hence, it is important to accurately identify whether you have EPS or TD before deciding on the right treatment.
Treating TD is more challenging than EPS. Available treatments have limited evidence supporting their success. The best course of action may be to stop taking the medication causing TD or to reduce the dosage, after discussing potential risks with your doctor. Some improvements in TD symptoms have been seen when patients switch to different antipsychotic medications, clozapine, and quetiapine specifically.
Benzodiazepines, a type of medication that enhances the activity of certain neurotransmitters in your brain, have been proposed as a potential treatment for TD. However, research doesn’t strongly support their effectiveness. Another possible treatment for localized TD could be using botulinum toxin, typically referred to as Botox, although this hasn’t been thoroughly studied. Encouraging advancements have been made using drugs known as VMAT2 inhibitors, including valbenazine, tetrabenazine, and deutetrabenazine, in alleviating the symptoms of TD.
The management of Neuroleptic Malignant Syndrome (NMS) – a serious condition induced by an adverse reaction to some types of antipsychotic medications, involves an immediate discontinuation of the suspected medication and firm medical support. This might include making sure your heart and lungs are functioning properly, maintaining normal body temperature and hydration levels, and trying to prevent complications like deep vein thrombosis (blood clots in deep veins), kidney failure, and heart rhythm problems. Certain medications (like dantrolene sodium or bromocriptine mesylate) may be beneficial in severe cases where there are high levels of muscle stiffness.
When dealing with a broad range of negative reactions to antipsychotic medications, it’s crucial to carefully balance the benefits and risks of continuing with the medication. If side effects are severe, but not life-threatening, and the benefits from using the medicine are obvious, doctors might recommend lowering the dose or altering the timing of the doses as a first step. If these measures aren’t effective, they may suggest trying a different medication, as many antipsychotic drugs are equivalent in effectiveness and mainly differ in their side effects. It’s important to mention, you shouldn’t change medications if there’s a high risk of relapse, such as in the case of people with treatment-resistant schizophrenia who have only responded to clozapine.
What else can Neuroleptic Agent Toxicity be?
Neuroleptic medication, a type of psychiatric drug, can have side effects that resemble various other conditions. For instance, seizures and stroke can give rise to abnormal, involuntary movements like dystonias. Parkinson’s disease, along with certain characteristics common in conditions like autism and schizophrenia, may also have similarities with the changes caused by neuroleptic usage.
In cases of an overdose, whether accidental or intentional, neuroleptics might mimic the effects of other drugs such as benzodiazepines, cyclic antidepressants, central alpha-2 agonists, antiepileptics, and skeletal muscle relaxants. The symptoms these drugs can cause are quite similar, making it challenging to identify which drug led to the overdose. A review of the patient’s medication history can be most helpful in such situations.
In some situations, patients on neuroleptic medications might appear excessively sleepy or delirious. This can be due to a range of causes, from hypoglycemia to infections of the nervous system, which need to be checked and ruled out.
One severe side effect of neuroleptic medications is Neuroleptic Malignant Syndrome (NMS), a life-threatening condition characterized by mental status changes and a high body temperature. Other conditions that can display similar symptoms include:
- Serotonin syndrome – a condition typically caused by drug interactions
- Salicylate toxicity – likely when a patient has overdosed on neuroleptic medication and aspirin-based drugs
- Sepsis – a severe infection that can also cause high body temperature and mental status changes
The symptoms of these conditions are quite similar to NMS and should be thoroughly investigated.
In cases where the cause for the patient’s symptoms is unclear, it’s important to also consider the following conditions:
- Anticholinergic toxicity
- Antidepressant toxicity
- Cocaine toxicity
- Antihistamine toxicity
- Selective serotonin reuptake inhibitor toxicity
- Delirium tremens
- Heat exhaustion
- Heatstroke
- Lithium toxicity
- Methamphetamine toxicity
- Status epilepticus
- Torsade de pointes (a type of irregular heart rhythm)
- Withdrawal syndromes
What to expect with Neuroleptic Agent Toxicity
In cases of recent overdose, FGAs (First-Generation Antipsychotics) and SGAs (Second-Generation Antipsychotics) generally have a similar outcome. Although muscle symptoms are less common with SGAs, the higher likelihood of it causing central nervous system depression (slowing of brain functionality) can potentially be more hazardous.
Death rates from NMS (Neuroleptic Malignant Syndrome – a rare reaction to antipsychotic drugs) differ widely according to various studies, ranging from 3.3% to 27.7%. However, there has been a decreasing trend over the last couple of decades. Fortunately, patients who survive an NMS episode usually recover fully. But, it’s worth noting that about 3% may experience long-term or permanent mental health complications.
Possible Complications When Diagnosed with Neuroleptic Agent Toxicity
EPS, or extrapyramidal symptoms, are conditions that can be treated in the short-term, and over time, can be reversed. Furthermore, they are unlikely to cause permanent damage. However, these symptoms might make a patient less willing to continue with their medication, making it more challenging to adhere to their treatment plan.
Taking second-generation antipsychotics (SGAs) may result in weight gain, which can increase the risk of heart-related health issues and even death. A high percentage of people with schizophrenia are overweight or obese and more likely to have diabetes compared to the general public. The weight gain that may come with taking SGAs can worsen this issue. A study of patients at a Veterans Administration site showed that those using SGAs had nearly two times the overall mortality rate due to an increased incidence of strokes, transient ischemic events, coronary artery disease, and heart failure.
Complications of NMS, or neuroleptic malignant syndrome, are due to the effects of the disease itself and the extended hospital stay and immobility that result. The most common complication of NMS is atraumatic rhabdomyolysis, which affects about a third of patients. Other usual complications include acute respiratory failure, kidney injury, blood clots in the veins, and widespread infections, which may be worsened by sepsis. Older patients, those with chronic heart failure, and those who develop acute respiratory failure, acute kidney injury, or sepsis, have a particularly high risk of death. Acute respiratory failure is the single strongest predictor of death. Long-term effects of NMS may include permanent Parkinson’s symptoms and cognitive dysfunction, from mild amnesia to severe cognitive impairment.
Effects of Mental Health Medications:
- May cause weight gain
- Potential increased risk of heart-related health issues
- Possible higher mortality rate
- Could develop conditions like stroke, transient ischemic events, coronary artery disease, or heart failure
Complications of NMS:
- Atraumatic rhabdomyolysis
- Acute respiratory failure
- Kidney injury
- Increased risk of blood clots
- Systemic infections made worse by sepsis
Potential Long-term Effects of NMS:
- Permanent symptoms of Parkinson’s disease
- Cognitive dysfunction, from mild amnesia to severe cognitive impairment
Preventing Neuroleptic Agent Toxicity
Many people often stop taking medication because they can’t handle the side effects. This happens even more frequently in those dealing with mental health issues. When starting drugs for neurological issues, it’s crucial for patients to understand the potential negative effects. These could be common side effects or even those that could be life-threatening. If patients start experiencing these symptoms, they should seek professional medical help instead of just stopping the medication on their own. It’s also important to note that most of these side effects don’t last forever and can be treated, which might help patients to stick with their medication plan.
