- Types of antipsychotics
- What are the side effects?
- What Are Antipsychotics?
- Common Antipsychotics
- Side Effects of Antipsychotics
- Antipsychotic Safety and Warnings
- Antipsychotics and Alcohol
- Antipsychotics and Pregnancy
- Like all medications, antipsychotics can come with side effects.
- 1. You might feel a bit drowsy.
- 2. You might feel a sense of restlessness.
- 3. You could gain some weight.
- Minimizing Cardiovascular Adverse Effects of Atypical Antipsychotic Drugs in Patients with Schizophrenia
Types of antipsychotics
Are there different types of antipsychotics?
Some people talk about two types of antipsychotic medication. Your doctor might call them the following.
- Typical or ‘first generation’. These medications have been used since the 1950s.
- Atypical or ‘second generation’. These medications have been used since the 1990s.
The main difference between these types is in their side effects. First generation antipsychotics may have more of an effect on your movement than newer ones. Although this does not mean newer generation antipsychotics don’t have any side effects on your movement.
This distinction can make it easier to talk about the different medications. But you should think about each antipsychotic individually. This is because everyone reacts differently to medication. You can never be certain how you will be affected by side effects or whether the medication will work for you. This can mean that the first medication you try may not be the right one for you.
If you have been on an antipsychotic for a few weeks and the side effects are too difficult to cope with, you should ask your doctor about trying a different one.
You can find more information about ‘Medication – choice and managing problems’ by clicking here.
Antipsychotic medication can come as tablets, a syrup or as an injection. The injections are called a depot. You may find a depot useful if you struggle to remember to take your medication, or might take too much. Your doctor should take your views into account when prescribing you medication.
We have listed the main types of antipsychotics below.
First generation antipsychotics (Typical)
The first generation of antipsychotics have been prescribed since the 1950s. The following medications are typical antipsychotics. They have been listed by their generic name with the brand name in brackets.
- Benperidol (Anquil)
- Chlorpromazine (Largactil)
- Flupentixol (Depixol)
- Fluphenazine (Modecate)
- Haloperidol (Haldol)
- Levomepromazine (Nozinan)
- Perphenazine (Fentazin)
- Pimozide (Orap)
- Sulpiride (Dolmatil, Sulpor)
- Trifluoperazine (Stelazine)
- Zuclopenthixol (Clopixol)
Second generation antipsychotics (Atypical)
The second generation of antipsychotics have been used more since the 1990s. Although some of them were developed before then. They have been listed by their generic name with the brand name in brackets.
Clozapine works slightly differently to others. It is sometimes given to people who are treatment resistant. This means other medication hasn’t helped their symptoms. The National Institute for Health and Care Excellence (NICE) says that people with schizophrenia should only be offered clozapine after having tried 2 other drugs.
Clozapine can cause your white blood cell numbers to drop, but this is rare. This could mean that you get infections more easily. If you take clozapine, you will need regular blood tests to make sure your white blood cell count is healthy.
If your white blood cell numbers start dropping, you will be asked to stop taking the medication. You will have another blood test after you have stopped clozapine to make sure they are back to normal. Your doctor might decide to change your dose of clozapine or offer you another type of medication.
National Institute Clinical Excellence (NICE) produce guidelines for the assessment and treatment of mental illnesses, such as psychosis and schizophrenia. There is a link to NICE at the end of this web page.
What are the side effects?
Your medication should come with a leaflet called a ‘patient information leaflet’. This leaflet will tell you what the side effects are and explain what to do if you are experiencing any side effects.
Side effects of antipsychotics can include the following:
- Stiffness and shakiness. This can often be reduced by lowering the dose. But, if a high dose is necessary, the shakiness can be treated with anticholinergic drugs. This is the same kind of medication that is used for Parkinson’s disease.
- Uncomfortable restlessness (akathisia).
- Movements of the jaw, lips and tongue (tardive dyskinesia).
- Sexual problems due to hormonal changes.
- Sleepiness and slowness.
- Weight gain.
- A higher risk of getting diabetes.
- Dry mouth.
- Blurred vision.
Not all antipsychotics will have these side effects. Second generation or atypical antipsychotics are less likely to cause movement side effects, but you might still experience them. If you do then your doctor might change your medication.
For a quick comparison of the type and severity of the side effects of some antipsychotics, look at the grid on page 6 of our antipsychotic factsheet. You can view this by clicking on the ‘download our antipsychotics factsheet’ link at the top of the page.
Physical health checks
Some antipsychotic medications can affect your heart. If you have a heart condition, or you are at risk of having difficulties with your heart, doctors might regularly check your heart. They might want to do this annually, or more regularly.
GP surgeries have a register of people with severe mental illness, such as psychosis or schizophrenia. If you are on the register your GP should offer you an annual physical health check. They might check your heart in these appointments.
Speak to your GP or psychiatrist if you want a heart check up before you start taking antipsychotics. Or have any concerns about your heart or blood vessels.
If you have psychosis and schizophrenia your doctor should offer to check your heart before you start antipsychotics if:
- the makers of your medication say you should,
- a physical health check has found you have a higher risk of heart or blood vessel problems, such as high blood pressure,
- you have heart or blood vessel problems or someone in your family has had them, or
- you have to go into hospital.
What Are Antipsychotics?
This class of drugs is used to treat a range of mental illnesses.
Antipsychotics are a group of drugs that are used to treat schizophrenia.
The medicines are also sometimes used to treat other mental illnesses, such as bipolar disorder, severe anxiety, or depression.
Older antipsychotics (known as “typical” antipsychotics) have been around since the mid-1950s.
Newer antipsychotics (known as “atypical” antipsychotics) were developed in the 1990s.
Antipsychotics work by blocking dopamine, a substance in the brain known as a neurotransmitter.
The medicines come as tablets, capsules, liquids, and depot (long-acting) injections. They’re marketed under various brand names.
Some common antipsychotics include:
- Chlorpromazine (Thorazine)
- Clozaril and FazaClo (clozapine)
- Risperdal (risperidone)
- Zyprexa (olanzapine)
- Seroquel (quetiapine)
- Geodon (ziprasidone)
- Abilify (aripiprazole)
- Invega (paliperidone)
- Latuda (lurasidone)
Side Effects of Antipsychotics
Side effects of antipsychotics may include:
- Rapid heartbeat
- Blurred vision
- Skin rash
- Sensitivity to sunlight
- Menstrual problems in women
- Weight gain or changes in metabolism
- Muscle spasms
Antipsychotic Safety and Warnings
Long-term use of typical (older) antipsychotic drugs may cause a serious and sometimes incurable movement condition called tardive dyskinesia (TD).
About 5 percent of people who take antipsychotics get TD each year, according to the National Institute of Mental Health.
Antipsychotics aren’t recommended for older adults with dementia, as these drugs may put them at increased risk for stroke and death.
The antipsychotic clozapine is highly effective, but it can cause a serious decrease in the number of white blood cells, which help your body fight off infections. Talk to your doctor about this risk.
Antipsychotics may also raise your risk of developing high cholesterol and diabetes.
Tell your doctor about all medical conditions you have before taking an antipsychotic.
Also, let your doctor know about all prescription, non-prescription, illegal, recreational, herbal, nutritional, or dietary drugs you’re taking.
Don’t drive or perform activities that require alertness until you know how the antipsychotic you’re taking affects you.
Follow the instructions on your prescription or package label carefully. Don’t take more or less of the drug than is recommended.
Don’t stop taking an antipsychotic without first talking to your doctor. Your doctor will probably want to take you off the drug gradually.
Keep all appointments with your doctor’s office and laboratory while taking an antipsychotic.
Your doctor will probably want to perform tests frequently to monitor your body’s response to the medicine.
Let your healthcare provider know that you’re taking an antipsychotic before having any type of surgery, including a dental procedure.
Antipsychotics and Alcohol
Alcohol can increase certain side effects of antipsychotics.
Avoid drinking alcohol while taking these medicines.
Antipsychotics and Pregnancy
Tell your doctor if you’re pregnant, or might become pregnant, before taking an antipsychotic.
Some antipsychotics may be safe to take during pregnancy, but you should discuss the benefits and risks of this with your doctor.
Also, talk to your healthcare provider before taking an antipsychotic if you’re breastfeeding.
Antipsychotics, as their name implies, are an important part of treating psychosis, a mental state often associated with schizophrenia and bipolar disorder, though they can also be prescribed for conditions such as severe depression, obsessive compulsive disorder (OCD), and post-traumatic stress disorder (PTSD). But, as with any drug, these medications can come with some side effects that aren’t necessarily obvious.
In general, antipsychotics primarily work by blocking or suppressing the brain’s dopamine D2 receptor, which is thought to be associated with symptoms of psychosis, Ananda Pandurangi, Ph.D., director of the Schizophrenia and Electroconvulsive Therapy programs at Virginia Commonwealth University’s Department of Psychiatry, tells SELF.
“In psychosis, when the patient is experiencing hallucinations, delusions, disorganized thinking and behavior, it is believed that these are driven by excessive dopaminergic activity,” Pandurangi says. “This hyperactivity is thought to be a result of hypersensitivity of the dopamine receptor, especially . The antipsychotic medications either block this receptor or reduce its activity.”
Like all medications, antipsychotics can come with side effects.
“While their benefit is thought to be largely related to their dopamine blocking or reducing effects, they have effects on other neurochemicals and receptors in the brain,” Pandurangi says. So, they can cause symptoms that reach beyond the main dopamine-related effects.
“The crucial thing is that anyone taking an antipsychotic, even at a relatively low dose, needs to be aware that there are side effects and needs to be working with a physician who they feel comfortable in contacting, should something come up,” Russell Margolis, M.D., clinical director of the Johns Hopkins Schizophrenia Center, tells SELF.
That said, not all antipsychotic drugs are associated with the same side effects. In general, older antipsychotic drugs (sometimes referred to as “first-generation,” “conventional,” or “typical”) tend to have more serious side effects and are more likely to cause side effects in general. But more modern atypical antipsychotics (also called “second-generation”) can also produce side effects.
Still, even within the category of atypical antipsychotics, some drugs are more likely to cause certain side effects (like weight gain) than others. And some people simply respond differently to specific drugs than others. So, no matter what medication you take, your mileage may vary.
Here are some of the potential side effects that you should keep in mind if you’re taking antipsychotics.
1. You might feel a bit drowsy.
Dr. Margolis says antipsychotics have a sedative quality that often causes drowsiness. In most patients, the effect is mild and temporary and might even be helpful for those who have difficulty sleeping.
But in other cases, this can, of course, be problematic if someone is experiencing excessive sleepiness during the day. If that sleepiness is making it difficult to do what you need to do during the day or interfering with your job, school work, or relationships, your doctor may be able to adjust your dose.
2. You might feel a sense of restlessness.
Antipsychotics may cause a side effect known as akathisia, which is a sense of motor restlessness that sometimes feels a lot like symptoms of anxiety.
“For some people with this side effect, it’s like having a motor running inside them that they can’t keep still, and sometimes it’s difficult to distinguish from people who are feeling anxious,” Margolis says.
3. You could gain some weight.
Dr. Margolis says that antipsychotics can increase your appetite, possibly leading to weight gain. In fact, a 2017 meta-analysis of clinical trials of antipsychotics found that almost all antipsychotics are associated with some level of weight gain after prolonged usage.
Minimizing Cardiovascular Adverse Effects of Atypical Antipsychotic Drugs in Patients with Schizophrenia
A professional function of a pharmacist is to provide drug therapy directed at definite outcomes that improve quality of life for patients. The profession of pharmacy has an obligation to the public to ensure that pharmacists provide safe, effective, timely, and compassionate care to patients. However, specialized areas may require specialized knowledge and skills, attained only through additional training.
Based on these considerations and given the shortage of primary care practitioners in general and in mental health/psychiatric facilities in particular, the present paper not only underscores but also provides guidance for the management of cardiovascular complications/manifestations in patients receiving treatment for schizophrenia.
2. Blood Pressure Changes
2.1. Hypotension and Orthostatic Hypotension
The definition of orthostatic hypotension is the decrease of 20 mmHg or more in systolic pressure or the decrease of 10 mmHg or more in diastolic pressure within three minutes of standing . Orthostatic hypotension is a common side effect of atypical antipsychotics. It is caused by anticholinergic or alpha-1 adrenoceptor blockage . Alpha-1adrenoceptors cause vasoconstriction in certain vascular beds. The blockade of these receptors leads to vasodilation which causes blood pressure to decline. This effect is mostly seen with blood pressure in the standing position, when sympathetic tone is important to maintain adequate blood pressure (Table 2). Prolonged effect of orthostatic hypotension has been associated with adverse outcomes such as stroke or myocardial infarction in severe cases.
Table 2 Assessment, monitoring, and patient education regarding orthostatic hypotension, hypertension, arrhythmias/torsades de pointes, and myocarditis in antipsychotic-treated patients.
Hypotension, including orthostatic hypotension, is a significant side effect encountered with atypical antipsychotic drugs. Adrenergic blockade may result in number of risks, such as syncope, falls, fractures, increased anginal episodes, and orthostatic hypotension. The agents that most commonly cause hypotension include clozapine, quetiapine, and risperidone. Olanzapine does not block alpha adrenergic receptors and has not been linked to orthostatic hypotension, although dizziness has been reported in some patients. Risperidone can occasionally cause orthostatic dizziness, hypotension including orthostatic hypotension, and reflex tachycardia. The least hypotensive effects are reported with ziprasidone. Atypical antipsychotic drugs in combination with cardiovascular medications such as methyldopa, diuretics, adrenergic blockers, calcium antagonists, angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, nitrates, and others may aggravate the hypotensive effects.
Orthostatic hypotension can contribute to the increase in risk for injury (i.e., hip fractures) and falls in the elderly population. This is because the elderly are frailer and have a higher incidence of osteoporosis compared to the younger population. It is recommended that those who take these psychotropic medications should be aware of dizziness. Recommendations of taking appropriate orthostatic blood pressure assessment are to have the patient lie supine for ten minutes, obtain blood pressure and heart rate, then take blood pressure and heart rate immediately after the patient arises, and ask about dizziness . Heart rate assessment will aid in differential diagnosis. Heart rate increases by 10–15 bpm normally on rising; in orthostatic hypotension, heart rate may increase (with a concomitant fall in blood pressure) within a range of 15–30 bpm. Next, have the patient maintain an upright posture for three minutes; then obtain blood pressure and heart rate again. Table 2 summarizes the key points for the assessment, monitoring, and patient education regarding orthostatic hypotension in antipsychotic-treated patients.
The SGAs that are associated with hypertension include clozapine, olanzapine, and ziprasidone. Quetiapine and risperidone appear to have the lowest risk of hypertension. Assessing the patient’s pre-existing illness and/or monitoring the patient’s blood pressure and heart rate at baseline and then periodically during treatment can help control and prevent further complications from arising. Table 2 summarizes the key points for the assessment, monitoring, and patient education regarding hypertension in antipsychotic-treated patients.
3. QTc Interval Prolongation and Torsades de Pointes
An electrocardiogram (ECG) measures the electrical activity of the heart and can serve as a diagnostic aid to determine possible heart complications. The phases of the ECG are summarized in Table 3. “P” waves show electrical currents moving towards the atrium of the heart, causing depolarization. When this occurs, there is a rapid influx of sodium ions that move into the cells through the sodium channel, while potassium ions are slowly moving out of the cell in the atria. It then produces a QRS complex that shows currents going to the ventricles causing depolarization. Similar to the “P” wave, sodium ions move into the cells while potassium ions are moving slowly out of the cell but that is in the ventricles. The calcium influx that follows causes the plateau of the action potential and helps myocardial contraction. The depolarization slows down in the ST segment. Finally, the “T” wave and “U” wave are associated with ventricular repolarization. The normal QTc intervals are approximately 400 msec or less. The greater the duration is, the more likely the ventricular arrhythmias may occur, especially if the interval is greater than 500 msec.
|TdP: torsades de pointes, a malignant form of ventricular arrhythmia, is polymorphic.|
Table 3 Phases of the electrocardiogram (ECG).
Torsades de pointes (TdP) is a polymorphic ventricular tachycardia associated with a prolonged QTc interval. The ECG pattern is distinctive and is called twisting because the peaks are at their smallest in one lead, and largest in another lead (Figure 1). Torsades de Pointes is often self-limiting, but when sustained can cause ventricular fibrillation and sudden death. Risk factors for TdP are female sex, history of heart disease, presence of a QT interval prolonging agent, hypokalemia, history of QT prolongation, family history of QT prolongation, QTc > 450 ms at baseline, and bradycardia (Table 4). Patients who have these risk factors should be monitored carefully or be taken off the drug entirely.
Table 4 Risk factors contributing to QTc interval prolongation and torsades de pointes.
Normal versus torsades de pointes ECG.
Potassium channels play an important role in ventricular arrhythmias (i.e., torsades de pointes). The potassium channel that is most involved in drug-induced QT syndromes is the potassium rectifier (Ikr) channel. Although olanzapine, quetiapine, and risperidone bind to the Ikr channel, it is unclear whether they cause TdP or not. Some of the psychotropic drugs that can possibly cause TdP are listed in Table 5 and include chlorpromazine, haloperidol, pimozide, thioridazine, mesoridazine, and ziprasidone.
Table 5 Antipsychotropic medications with potential risk for QTc interval prolongation.
The first generation antipsychotic thioridazine, even at therapeutic dosages, is frequently cited as causing TdP and sudden death by blocking the potassium channel Ikr and prolonging the QT interval . It is recommended that the lowest dose possible be given to patients with cardiovascular problems because higher doses could cause repolarization abnormalities. This medication is contraindicated in patients who are at risk for TdP.
Ziprasidone has some effect on repolarization, but it is not dose dependent. It prolongs QT interval more than haloperidol, olanzapine, quetiapine, and risperidone but less than sertindole and thioridazine . In premarketing trials, an increased risk of arrhythmia was not associated with ziprasidone; however, this does not assure complete safety from causing any arrhythmias .
In one study, the cardiac effects of haloperidol, olanzapine, quetiapine, risperidone, thioridazine, and ziprasidone were compared. Results showed that thioridazine had the longest QTc interval prolongation, followed by ziprasidone, quetiapine, risperidone, olanzapine, and haloperidol (35.6 ms, 20.3 ms, 14.5 ms, 11.6 ms, 6.8 ms, and 4.7 ms, resp.) . Not all drugs with longer QTc interval have a higher risk of torsades. For example, risperidone has a higher QTc interval compared to haloperidol, but haloperidol has been known to cause TdP and sudden death more than risperidone . Measuring the QTc interval of patients is a way to determine the risk of having torsades; however, it should not be used as the only determining factor. Table 6 lists the relative risk of QTc interval prolongation with common antipsychotic agents.
Table 6 Relative risk of QTc interval prolongation with common antipsychotic agents.
In this connection, there have been case reports providing evidence for the association of ziprasidone with torsades de pointes . For example, in one case, a 30-year-old woman with a medical history of mental retardation and depression with psychotic features was found unresponsive by emergency medical technicians. Since her regular medications included ziprasidone, after examination, it was concluded that the ziprasidone may have contributed, in part, to her torsades de pointes episode . In a separate case study, a 28-year-old Hispanic woman with a history of mental diseases and on multiple medications including ziprasidone and lithium was admitted to the intensive care unit (ICU). Upon evaluation, her QT interval was found to be prolonged. Given that the patient was on lithium, ziprasidone, and hypokalemic on presentation, which are all risk factors for QT-interval prolongation and progression to torsades de pointes, the episode of torsades de pointes was attributed only in part to ziprasidone .
Assessment and monitoring of patients are needed to determine their wellness. Determining the patient’s history of heart disease (including family members) and inquiring about other types of psychotropic, heart, or over-the-counter medications are needed to start any drug therapy. A thorough physical examination and ECG monitoring are important in determining the heart rate and blood pressure. Lastly, taking blood samples periodically is needed to determine patient’s potassium levels. It is important because low levels of potassium can increase the risk of TdP. Table 2 summarizes the key points for the assessment, monitoring, and patient education regarding arrhythmias/torsades de pointes in antipsychotic-treated patients.
4. Sudden Death
There is no known mechanism on how sudden death occurs, but it is known that it may possibly be caused by cardiac arrhythmias, notably TdP following ventricular fibrillation. The common feature is delayed repolarization of the myocardium which causes a prolongation of the QT interval of the ECG. This leaves the myocardium vulnerable to ventricular tachycardia and in some serious cases sudden death.
A study by Ray and his colleagues followed nearly 0.5 million Tennessee Medicaid enrollees for 2.5 years and found 1,487 sudden deaths due to heart problems, or an incidence of 11.6/10,000 person-years. Patients who received antipsychotic drugs, in doses of more than 100 mg of thioridazine or its equivalent, had 2.39 times higher risk of having sudden death compared to nonusers (95% CI = 1.77–3.22). It has been shown that risperidone can prolong QTc interval although reports of sudden death are rare . Sudden death can be contributed to various physical and psychological factors: age, pre-existing heart condition, frequency of prolonged smoking, generic disorder of calcium channels, metabolism of antipsychotic drug, schizophrenia itself, and the use of drugs such as thioridazine, droperidol, haloperidol, pimozide, and sulpiride. There is also some evidence that shows schizophrenic patients having higher risk for sudden death regardless of taking any medications. This increased risk of sudden death can be due to the schizophrenic illness itself or a combination of other factors such as lifestyle (e.g., smoking, poor diet, and general neglect of health) and poor access to medical care .
Myocarditis, inflammation of the heart muscle, is a rare complication of clozapine therapy. In one study, the estimated incidence was between 0.7% and 1.2% of clozapine-treated patients . The mechanism is unknown but it is suggested that it could be IgE-mediated hypersensitivity to exposure to chemicals or certain medications. When the heart muscle becomes inflamed and weakened, it causes lymphocytic infiltration and other symptoms similar to heart failure, which then may mimic a heart attack. However, it rarely causes sudden death. Symptoms of myocarditis are similar to congestive heart failure. They include fever, chest pain, joint pain or swelling, abnormal heart beats, fatigue, shortness of breath, fainting, low urine output, leg swelling, and the inability to lie flat. Sometimes, no symptoms are present at all.
Myocarditis can be detected from a physical exam showing irregular and/or abnormal heart beats or sounds, fluids in the lungs, skin, and/or the legs. Other examinations include ECG, chest X-ray, WBC, RBC, and blood cultures for infections. Treatment includes an evaluation and treatment of the underlying problem. This may require use of antibiotics for infection and low-salt diet to avoid retaining water. Diuretics are also given to remove body water. Steroids and anti-inflammatory medications are used to reduce inflammation. Abnormal heart rhythm may require the use of additional medications, a pacemaker, or even a defibrillator. If a blood clot is present in the heart chamber, anticoagulants may be given as well. It is important to treat as soon as possible to prevent complications such as heart failure, pericarditis, or cardiomyopathy.
Clozapine, which is (the only drug) indicated for resistant schizophrenia, has a “black box” warning for causing an increased risk of fatal myocarditis. One study reported 23 cases (20 men, three women; mean age 36 years) of clozapine-associated cardiovascular complications: 15 of myocarditis and eight of cardiomyopathy . Of the 23 patients, six died (five deaths from myocarditis). All cases of myocarditis occurred within three weeks of starting clozapine. Of the eight cases of cardiomyopathy, the condition was diagnosed up to 36 months after initiation of clozapine. Necropsy findings showed mainly eosinophilic infiltrates with myocytolysis (consistent with an acute drug reaction). Therefore, clozapine therapy may be associated with potentially fatal myocarditis and cardiomyopathy in young adults with schizophrenia. Clozapine should be discontinued if a patient has an onset of fatigue, dyspnea, tachypnea, fever, chest pain, palpitations, heart failure symptoms, arrhythmias, or ECG abnormalities. Patients should be aware of these side effects so they can let their physicians know right away to discontinue the medications. Table 2 summarizes the key points for the assessment, monitoring, and patient education regarding myocarditis in antipsychotic-treated patients.
Antipsychotic medications can cause various types of cardiovascular complications (e.g., arrhythmias, hypertension, myocarditis, and orthostatic hypotension). Increased awareness of these potential complications can allow pharmacists and clinicians to better manage and monitor at-risk patients. Accurate assessments are very important to avoid medications from being given to patients inappropriately. In addition, monitoring patients regularly via blood draws and checking blood pressure, heart rate, respiration rate, and ECG can also help catch any clinical problems as well as prevent further complications from occurring. Lastly, educating patients, family, and caregivers on what to look out for and how to handle certain side effects is very important. By doing so, the risk of mortality for patients with mental and behavioral disorders may be further reduced. Pharmacists practicing in mental health facilities, by virtue of their job functions and responsibilities, are in a unique position to play a pivotal role in minimizing the cardiovascular adverse effects of antipsychotic drugs.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
This work was supported by funds from the College of Pharmacy, Western University of Health Sciences (to Gollapudi S. Shankar).