Iloperidone, a derivative of piperidinyl-benzisoxazole is an atypical antipsychotic drug. It is a trademark for the Vanda Pharmaceuticals and was recently approved by the Food and Drug Administration for acute treatment of schizophrenia in acute stage in the adults (Bishop, Bishop, & Jennifer Zacher, 2011). This drug requires a slow dose titration which delays its efficacy in the first two weeks. This is in agreement with the FDA-approved labeling. It requires adjustments of doses to reduce the risk of orthostasis. The slow rate of adjusting dosage makes it a less ideal agent for treating acute exacerbations of schizophrenia. Iloperidone is purely antagonistic and its behavior has been evaluated using animal models. The drug was initially disapproved due to its inefficacy and various adverse effects together with risks associated with it such as in dementia-related psychosis and QTc elongation.
It binds with high antagonistic affinity to serotonin 5-HT1A, 5-HT2A and dopamine D2 and D3 receptors and moderately interacts with dopamine D4, serotonin 5-HT6 and 5-HT7 and adrenergic α1 and α2 receptors (Arif & Mitchell, 2011).
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Drug Use in Animal Models
To make a comparison on iloperidone behavior with other known antipsychotics, the drug was evaluated in pharmacological models and a single developmental model of disrupted Pre-pulse inhibition (PPI) in rats. Iloperidone has behavioral effects in pharmacological models of disrupted sensorimotor gating consistent with “atypical” antipsychotics, which is mediated by antagonism of noradrenergic and dopaminergic receptors.
In vitro, iloperidone has an affinity to bind to the dopamine and serotonin receptors. Initially, this was the basis for its selection. The affinity at the D2 sites is weaker while the affinity for the 5-HT2 receptors in rats is higher. The affinity for the rat’s alpha-1 noradrenergic receptors is also lower. In isolated dog Purkinje fibers, iloperidone has the capability to prolong the duration of the action potential and blockage of hERG currents and therefore result in prolongation of the QTc interval (Corbett et al., 1997). A hemodynamic evaluation carried out on dogs and rats indicated that iloperidone lowers the blood pressure in a dose-dependent manner and also raises the heartbeat. However, it did not have any effect on the ECG parameters or the cardiac output.
Additionally, no adverse effects were found on the respiratory system. Animals species tested for the oral and intravenous administration of the drug indicated that the drug was rapidly absorbed even though the bioavailability was lower as a result of the first pass metabolism effect. Studies on the general toxicity of the drug and its P95 metabolite were done on mice, rats, and dogs (Corbett et al., 1997). The outcome of these tests in rats was decreased weight, hematological changes and changes in the males and females’ mammary glands. Oral administration in dogs caused loss of weight and adverse neurological clinical signs. Iloperidone shows a potent antipsychotic activity in various animal models which predicts its efficiency against positive symptoms of schizophrenia. An example of such behavioral models is antagonism of climbing behavior of a mice that is induced with apomorphine (Corbett et al., 1997).
Iloperidone had the perfect chance of distinguishing its efficacy at the higher doses, but the FDA wanted to ensure that the side effects did not start kicking in. The specific indication for the drug is alleviation of psychotic symptoms and not schizophrenia (Vigneault, Pilote, Patoine, Simard, & Drolet, 2012). This is a noteworthy difference from the standard indications for the recently enlisted antipsychotic drugs as these indicate a clinical condition as opposed to a symptom happening in patients who have a clinical condition (for this situation, schizophrenia). This is the approach suggested in the TGA adopted European Union (EU) rule. The efficacy and safety of the drug in schizophrenic patients in comparison to the active risperidone used in previous studies was of great concern to the FDA. The drug was disapproved as more trials were needed to compare iloperidone with placebo and another active comparator like olanzapine with the aim of demonstrating the further efficacy of the drug (Weiden, 2012). Also for doses ranging from 20 to 24 mg/day, safety data had to be obtained by the Vanda Pharmaceuticals for the patients. There are many risks associated with this drug. This includes neurological symptoms especially among the elderly, cardiovascular risks and metabolic changes. With all these risks, physicians would have opted to prescribe other antipsychotic drugs as first line treatment before prescribing iloperidone. The risks are:
Increased rates of mortality cases in elderly patients who have dementia-related psychosis. Iloperidone is not approved by the Food and Drug Administration (FDA) to be used in such patients (Arif & Mitchell, 2011).
Neuroleptic Malignant Syndrome
This fatal syndrome has been associated with the administration of antipsychotic drugs and more so iloperidone. This syndrome manifests as altered mental status, muscle rigidity, autonomic instability including tachycardia, cardiac dysrhythmias, and hyperpyrexia (Bishop, Bishop, & Jennifer Zacher, 2011). It also results in elevation of creatine phosphokinase and acute renal failure.
This drug is associated with metabolic changes that result in increases cardiovascular risks. Some of these changes are dyslipidemia and hyperglycemia. Patients who have been treated with iloperidone have reported instances of hyperglycemia in association with ketoacidosis in extreme cases or even hyperosmolar coma or death (Arif & Mitchell, 2011). There is an increased risk of diabetes mellitus in patients who are suffering from schizophrenia. This changes in glucose levels together with undesirable alteration in lipids makes iloperidone not an ideal choice of drug for psychotic patients.
Any drug that is a dopamine D2 receptor antagonists, e.g., iloperidone results in elevations of prolactin levels. Hyperprolactinemia causes suppression of GnRH in the hypothalamus thus lowers gonadotropin secretion from the pituitary. This may inhibit the reproductive function in male and the female patients. Also, amenorrhea, galactorrhea, and gynecomastia have been associated with altered prolactin levels.
Orthostatic Hypotension and Syncope.
Due to its alpha one adrenergic antagonist properties, iloperidone induces orthostatic hypotension which is accompanied by tachycardia, syncope, and headache. This is why it is contraindicated in patients who have known cardiovascular diseases such as heart failure and myocardial infarction or any other condition that puts the patient at a risk of developing hypotension such as hypovolemia and dehydration.
A QTc study done on patients with schizophrenia showed that there was a significant prolongation of QTc. This is attributed to the presence of CYP450 2D6 metabolic inhibition. Hence the use of iloperidone is contraindicated with other drugs that also prolong QTc such s antiarrhythmic medications, antibiotics like gatifloxacin or others like methadone and pentamidine (Corbett et al., 1997). Iloperidone is also not used in patients who have congenital long QT syndrome and those who have cardiac arrhythmias. There is also an increased risk of Torsade de Pointes or sudden death with use of this drugs. Patients who are being treated with this drug and have a great risk for developing electrolyte imbalance ought to have periodic monitoring of the potassium and magnesium levels.
This is a syndrome that consists of involuntary and irreversible dyskinetic movements that may develop if the patient is treated with iloperidone. This is more prevalent in elderly females who are under the medication (Weiden, 2012). The probability of becoming irreversible is a consequence of increased duration of using the drug which results in increased total cumulative dose.
The side effects of the drug include extrapyramidal symptoms such as Parkinsonism, Tremor, dystonia, bradykinesia and akathisia. Short term dose-related sedation has also been associated with iloperidone (Weiden, 2012). This effect is consistent with the weak affinity that the drug has for H1 receptors, though this is relatively comparable to other antipsychotic drugs. From various studies carried out, most weight is gained during the first six weeks. It is a dose-dependent effect of higher doses of 20-24 mg causing more weight gain. Iloperidone is an alpha- adrenergic blocking agent and as a result, it induces priapism. Psychotic patients have a high tendency of attempting suicide. When administering these drug to a high-risk patient, close supervision should be carried out to ensure that there no incidence of a drug overdose which may prompt suicide.
Like any other antipsychotic drug, iloperidone can cause judgment or motor skills impairment. The physician should caution the patient not to operate heavy machinery such as automobiles until the adverse effects of the drug are very minimal. Some of the gastrointestinal effects of the drug include dry mouth, nausea, diarrhea, dysphagia and salivary hyper secretion. Musculoskeletal effects include musculoskeletal stiffness, arthralgia muscle spasms, and difficulty in walking. One can also develop rashes and on the genitourinary system, the drug can result in ejaculation failure, lowering of libido, erectile dysfunction, and urinary retention. Hematological effects include agranulocytosis, neutropenia and iron deficiency anemia (Vigneault, Pilote, Patoine, Simard, & Drolet, 2012). It also results in fatigue, hyperthermia, and edema in the body as a whole. The effects in the central nervous system are dizziness, somnolence, delusions, vertigo, restlessness and aggression.
Food and Drug Administration (FDA) approved Iloperidone in May 2009. The drug’s evaluation on its efficacy, safety and tolerability led to the approval and it was based on three placebo-controlled clinical trials. In all the clinical studies, iloperidone was more superior to the placebo in the Positive and Negative Syndrome Scale (PANSS) total score (Bishop, Bishop, & Jennifer Zacher, 2011).
Genetic testing has a major role when it comes to making pharmacotherapy decisions. Iloperidone will have additional efficacy benefits of defined genetic testing. This will be a form of new life for the drug. In the coming years, a depot formulation will be available to aid in adherence to treatment. Most schizophrenic patients usually stop taking medications. Many discontinue their therapy after being discharged. This new formulation will improve the patients’ adherence since it will only be given every two or four weeks.
In conclusion, iloperidone is a safe and viable treatment option for schizophrenic patients especially the adults who are not able to tolerate other antipsychotic agents. However, the drug does not have defined benefits over the other antipsychotic drugs.
Arif, S. & Mitchell, M. (2011). Iloperidone: A new drug for the treatment of schizophrenia. American Journal Of Health-System Pharmacy, 68(4), 301-308
Bishop, Bishop, & Jennifer Zacher,. (2011). Iloperidone: Efficacy Review for the Acute Treatment of Schizophrenia in Adults. Clinical Medicine Reviews In Therapeutics, 279. http://dx.doi.org/10.4137/cmrt.s1538
Corbett, R., Griffiths, L., Shipley, J., Shukla, U., Strupczewski, J., & Szczepanik, A. et al. (1997). Iloperidone: Preclinical Profile and Early Clinical Evaluation. CNS Drug Reviews, 3(2), 120-147. http://dx.doi.org/10.1111/j.1527-3458.1997.tb00320.x
Vigneault, P., Pilote, S., Patoine, D., Simard, C., & Drolet, B. (2012). Iloperidone (Fanapt®), a novel atypical antipsychotic, is a potent HERG blocker and delays cardiac ventricular repolarization at clinically relevant concentration. Pharmacological Research, 66(1), 60-65. http://dx.doi.org/10.1016/j.phrs.2012.03.008 Weiden, P. (2012). Iloperidone for the Treatment of Schizophrenia: An Updated Clinical Review. Clinical Schizophrenia & Related Psychoses, 6(1), 34-44. http://dx.doi.org/10.3371/csrp.6.1.5