Antipsychotic abuse refers to the non-medical or inappropriate use of antipsychotic medications for purposes other than their intended therapeutic use. Antipsychotics, also known as neuroleptics, are a class of medications primarily used in treating psychiatric disorders such as schizophrenia, bipolar disorder, and certain types of depression.
The misuse and abuse (MUA) of pharmaceuticals are typically linked to medications that elicit euphoria or other desirable effects, such as relaxation or increased alertness. Consequently, antipsychotics are not commonly categorized as significant substances prone to abuse. However, antipsychotics abuse may be attributed to its calming and sedative effects, and they have been exploited to either enhance the effects of illicit substances like cocaine and marijuana or counteract their adverse consequences. Due to the potential of physical, social, and psychological consequences in patients using antipsychotics, the prevention and protection of these patient populations from the MUA of drugs has been implemented via various legislations worldwide which differ depending on the local jurisdiction.
Classifications Types of abuse Individuals may misuse and abuse antipsychotics for various reasons, including recreational purposes, self-medication, or attempting to alter their mental or emotional state. The most common forms of antipsychotic abuse may include non-prescribed use, which involves the use of antipsychotic medications without a valid legal prescription or the absence of medical supervision. This can involve obtaining medication from other individuals, sharing prescription drugs, or acquiring them through illicit means.
Additionally, the misuse of prescribed medication can also involve using antipsychotics in a manner inconsistent with the prescribed indications. This includes taking higher dosages than recommended, increasing the dosing frequency, using them for longer durations than the prescribed treatment timespan as well as using medications prescribed to someone else. The combined or concurrent use of antipsychotics with other substances to enhance or alter the effects is also considered a form of abuse. This can involve combining them with alcohol, illicit drugs, or other prescription medications, which can have unpredictable and potentially dangerous interactions.
Classification of antipsychotics
There are two categories of oral antipsychotic drugs: typical; the first-generation antipsychotics and atypical; the new generation. Typical antipsychotics include Chlorpromazine, Fluphenazine, Haloperidol, and Trifluoperazine. Atypical antipsychotics include Amisulpride, Aripiprazole, Clozapine, Olanzapine, Paliperidone, and Quetiapine. Alt URL While both types of antipsychotic drugs are effective, the main differences are that atypical ones generally have fewer side effects compared to typical ones. These side-effects may include the onset of extrapyramidal motor symptoms which in the long term may cause a condition called tardive dyskinesia, which involves involuntary movements of the mouth, tongue, face, jaw, and sometimes other body parts. Atypical antipsychotics have also shown an increased risk of weight gain, diabetes, and cardiovascular disease.
Reasons for abuse and affected populations The misuse of atypical antipsychotics can be attributed to various factors. From a pharmacological perspective, the involvement of neurotransmitter systems such as serotonin, histamine, and α-adrenergic systems is of significant importance. Quetiapine, a specific second-generation antipsychotic (SGAP), exhibits distinct pharmacological effects depending on the dosage administered. At lower doses, it primarily acts as an antagonist for histamine (H1) and serotonin receptors, resulting in an elevation of synaptic serotonin levels. This mechanism contributes to the sedative effects associated with H1 antagonism and the anxiolytic effects mediated by α-blockade. These sedating and anxiolytic properties are considered to be the primary drivers of misuse.
Results from a study which analysed the World Health Organization (WHO) Global Individual Case Safety Report (ICSR) database VigiBase, a worldwide pharmacovigilance database on antipsychotic misuse, show that out of a total of 2096 ICSRs which fall under the subgroup of “Drug abuse, dependence and withdrawal”, 1683 involved SGAPs (80%), mainly quetiapine (1089 ICSRs) and olanzapine (209 ICSRs). Further analysis showed that the major characteristics of quetiapine misuse mainly involved women with a mean age of 47 ± 15 years and olanzapine misuse mainly associated with men with a mean age of 43 ± 14 years. The study also noted that the trend in the misuse of SGAPs from 1993 to 2017 started to increase from 2009 with a peak in 2015 which confirms the significance of misuse in recent years.
Outcomes of abuse involved severe outcomes, such as hospitalisation or prolonged illness, mortality, life-threatening risks, and lasting effects. Within the VigiBase ICSRs, reasons for misuse included the off-label usage of SGAPs for sleeping disorders, and anxiety. Combining quetiapine or olanzapine with other medications included antidepressants, opioids, and anxiolytics. Additionally, both drugs have been found to be used in combination with illicit substances, primarily heroin and cocaine.
Indicators of the escalating street value of SGAPs is evident in the growing number of street names associated with the two drug, including quell, Susie Q, baby heroin, and squirrel for quetiapine and Zy for olanzapine. The black market value for quetiapine tablets are being sold illicitly at prices ranging from $3 to $8 per tablet. There has also been reports of both drugs extending past the traditional oral route of administration to using it intra-nasally (snorting) and injection also known as Q-ball which is the concomitant administration of cocaine with quetiapine.
Signs and symptoms The wide variability in the toxic and lethal doses of antipsychotics is largely dependent on factors such as the actual drug compound, patient age, weight and the presence of co-intoxicants. However, the most frequent clinical presentations revolve around Central nervous system (CNS) effects, extrapyramidal side effects (EPS) and neuroleptic malignant syndrome which is more commonly seen in children. CNS side effects include: Miosis, rapid mood fluctuations (depression and agitation), seizures and coma. Anticholinergic side effects include: blurred vision, dry mouth, facial flushing and decreased sweating. Some cardiopulmonary side effects include: Tachycardia, palpitations, respiratory depression, and chest pain. +Adverse effects of antipsychotic medicationsKeepers GA, Fochtmann LJ, Anzia JM, et al. The American Psychiatric Association practice guideline for the treatment of patients with schizophrenia. American Psychiatric Association 2020. Available at: https://www.psychiatry.org/psychiatrists/practice/clinical-practice-guidelines (Accessed on April 7, 2024)Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs – Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2). Available at: .Weight gainParkinsonismTardive DyskinesiaSedationAnticholinergicQTc prolongationFirst-generation antipsychoticsChlorpromazine ++ ++ +++ +++ +++ +++Fluphenazine ++ +++ +++ + + +Haloperidol ++ +++ +++ + +Oral: ++ IV: +++Trifluoperazine ++ ++ ++ + ++n/aSecond-generation antipsychotic agents Aripiprazole + + + + +n/aClozapine +++ + + +++ +++ ++Olanzapine +++ ++ + +++ ++ ++Paliperidone ++ ++ ++ + + +Quetiapine ++ + + +++ ++ ++(+): Mild significance, (++): Moderate significance (+++): Strong significance
Assessment and Treatment Total Daily Dose (TDD) Calculator The TDD is a tool used to assess potential antipsychotic misuse. It allows clinicians to calculate the total daily dosage of antipsychotic medications prescribed to patients based on guidelines from the British National Formulary (BNF).
The calculator determines a patient's TDD by accounting for the specific antipsychotic drug(s), dosing frequency, and dosage amounts for both monotherapy (single drug) and polypharmacy (multiple drugs). It then compares the calculated TDD to standard dosing recommendations in the BNF.
If the TDD exceeds guidelines outlined in the BNF or if the combination of individual drug dosages exceeds 100% of the maximum recommended daily amounts, the calculator flags this as a high dosage regimen which could indicate antipsychotic misuse or over prescription. By objectively quantifying total dosage levels, the TDD Calculator aims to help clinicians evaluate prescribing practices and identify situations where dosage reductions may be warranted to minimize health risks for patients.
General Management of Antipsychotic Overdose Currently, there is no specific antidote for the treatment of antipsychotic overdose. The general protocol for the treatment of antipsychotic overdose involves primary supportive care, decontamination with enhanced elimination techniques such as using gastric lavage and activated charcoal. Specific anticholinergic side effects can be targeted by using anti-cholinergic agents. Every patient should be on continuous cardiac monitoring with an ECG done, intravenous (IV) access, and the constant reevaluation of changes in mental state.
Primary supportive care protocol involves the ABC approach which focuses on reversing any signs of airway obstruction (A), ensuring respiratory rate and breathing parameters are normal (B) and to assess the circulation of blood is normal to prevent hypovolemic shock (C). Whenever the patient is hemodynamically stable, a single dose of activated charcoal is recommended. The onset of acute extrapyramidal symptoms due to antipsychotic overdose can be treated with anticholinergic agents, such as diphenhydramine or benztropine. Patients with neuroleptic malignant syndrome require supportive care, include active cooling to prevent overheating, benzodiazepines, bromocriptine, or neuromuscular blockade, depending upon the severity of symptoms.
Societal Impacts Antipsychotic abuse has grown increasingly more prevalent worldwide and has brought about various negative impacts to the society.
Death and Hospitalization In the study examining 1683 patients with second-generation antipsychotic misuse extracted from WHO pharmacovigilance database, 24% were hospitalized. More importantly, the death rate was at 28%, which was higher than that of hospitalization by 4%. This means that patients may risk of death before arriving at the hospital to receive any treatments with the misuse of SGAPs.
In addition to the high mortality rate, extra hospital services and medical resources were allocated to offset the negative effects of antipsychotic MUA. Research shows that non-adherence to antipsychotic medication would lead to increased number of relapses, being persistent psychotic and an enhanced risk of hospital admission in psychotic conditions. For instance, in a schizophrenic patient study group that assumes 90% of them comply to their medication at inclusion, more than 50% of the patients admitted to the hospital were non-compliant to their at-home antipsychotic dosage regimen. By contrast, adherent patients tend to have better medical outcomes and improvements in Global Assessment of Functioning level across the two years.
Adverse reactions and suicidal attempt In general, there were several issues posed by antipsychotic abuse with regards to their adverse reactions.
Antipsychotic polypharmacy would increase frequency of adverse effects, and A longer duration of treatment results in more severe the adverse reactions (e.g. high BMI) Some antipsychotics are more associated with specific metabolic disturbances (e.g. Clozapine)