Clozapine-Induced Gastrointestinal Hypomotility: A 22-Year Bi-National Pharmacovigilance Study of Serious or Fatal ‘Slow Gut’ Reactions, and Comparison with International Drug Safety Advice

The benefits of antipsychotic medications are sometimes obscured by their adverse effects. These effects range from relatively minor tolerability issues (e.g., mild sedation or dry mouth) to very unpleasant (e.g., constipation, akathisia, sexual dysfunction) to painful (e.g., acute dystonias) to disfiguring (e.g., weight gain, tardive dyskinesia) to life-threatening (e.g., myocarditis, agranulocytosis). Importantly, adverse effect profiles are specific to each antipsychotic medication and do not neatly fit into first- and second-generation classifications. This paper reviews management strategies for the most frequent side effects and identifies common principles intended to optimize net antipsychotic benefits. Only use antipsychotics if the indication is clear; only continue antipsychotics if a benefit is discernible. If an antipsychotic is providing substantial benefit, and the adverse effect is not life-threatening, then the first management choice is to lower the dose or adjust the dosing schedule. The next option is to change the antipsychotic; this is often reasonable unless the risk of relapse is high. In some instances, behavioral interventions can be tried. Finally, concomitant medications, though generally not desirable, are necessary in many instances and can provide considerable relief. Among concomitant medication strategies, anticholinergic medications for dystonias and parkinsonism are often effective; beta-blockers and anticholinergic medications are useful for akathisia; and metformin may lead to slight to moderate weight loss. Anticholinergic drops applied sublingually reduce sialorrhea. Usual medications are effective for constipation or dyslipidemias. The clinical utility of recently approved treatments for tardive dyskinesia, valbenazine and deutetrabenazine, is unclear.

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“…Constipation due to antipsychotics, particularly clozapine, can be severe and can lead to ileus. Prevention and early recognition are critical.…”

Section: Specific Adverse Effectsmentioning

confidence: 99%

Management of common adverse effects of antipsychotic medications

2018

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“…Online supplementary Box S11 [49, 68,[188][189][190][191][192][193][194][195][196][197][198][199][200][201][202][203][204][205][206][207] explains that our VigiBase search [49] provided another four definitive clozapine ADRs associated with fatal outcomes: (1) constipation, (2) arrythmia, (3) seizures, and (4) syncope.…”

Section: Other Potentially Lethal Clozapine Adrsmentioning

confidence: 99%

A Rational Use of Clozapine Based on Adverse Drug Reactions, Pharmacokinetics, and Clinical Pharmacopsychology

Leon

Ruan

Schoretsanitis

et al. 2020

Psychother Psychosom

121

113

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Using Richardson and Davidson's model and the sciences of pharmacokinetics and clinical pharmacopsychology, this article reviewed the: (1) poor life expectancy associated with treatment-resistant schizophrenia (TRS), which may be improved in patients who adhere to clozapine; (2) findings that clozapine is the best treatment for TRS (according to efficacy, effectiveness and well-being); and (3) potential for clozapine to cause vulnerabilities, including potentially lethal adverse drug reactions such as agranulocytosis, pneumonia, and myocarditis. Rational use requires: (1) modification of the clozapine package insert worldwide to include lower doses for Asians and to avoid the lethality associated with pneumonia, (2) the use of clozapine levels for personalizing dosing, and (3) the use of slow and personalized titration. This may make clozapine as safe as possible and contribute to increased life expectancy and well-being. In the absence of data on COVID-19 in clozapine patients, clozapine possibly impairs immunological mechanisms and may increase pneumonia risk in infected patients. Psychiatrists should call their clozapine patients and families and explain to them that if the patient develops fever or flu-like symptoms, the psychiatrist should be called and should consider halving the clozapine dose. If the patient is hospitalized with pneumonia, the treating physician needs to assess for symptoms of clozapine intoxication since halving the dose may not be enough for all patients; consider decreasing it to one-third or even stopping it. Once the signs of inflammation and fever have disappeared, the clozapine dose can be slowly increased to the prior dosage level. 46, 48, 52-67] describes the important pharmacokinetic variables for clozapine clearance. Higher clozapine C/D ratios, indicating lower clearance, are associated with females, non-smokers, Asians, genetic poor metabolizers, inhibitors, obesity, inflammation, and possibly with renal impairment and pregnancy. Lower clozapine C/D ratios indicate lack of adherence or higher clearance associated with males, smokers, non-Asians, and inducers.Two prior TDM review articles [68,69] are summarized in online supplementary Box S3 [31, 44, 50, 51, 55, 58-61, 63, 65, 68-91] which also describe our extensive experience with thousands of inpatient clozapine TDMs under standard conditions (trough and steady-state levels) in the US [44] and China [45,65]. Many of these inpatients were followed for months and/or years after changes in important pharmacokinetic variables [31, 44, 50, 58-61, 63, 65, 74, 79, 86-91].Published review articles [92][93][94] usually insist on the wide variability of clozapine TDM among individuals and the difficulty of interpreting a single clozapine level, but they fail to pay attention to findings from these two sciences: pharmacokinetics and clinical pharmacopsychology, which help in interpreting variability in clozapine levels. In inpatients, repeated measures allow the calculation of average clozapine clearance in an individual through a...

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“…Up to 9% of total death rate was reported and out of 177 cases 20% of cases of NMS with patients aged 18 years or younger were reported as serious adverse drug reactions. 43,44,45…”

Section: G Neuroleptic Malignant Syndromementioning

confidence: 99%

Psychotic Disorders, Definition, Sign and Symptoms, Antipsychotic Drugs, Mechanism of Action, Pharmacokinetics & Pharmacodynamics with Side Effects & Adverse Drug Reactions: Updated Systematic Review Article

Bangwal

Bisht

Saklani

et al. 2020

J. Drug Delivery Ther.

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Psychosis is a mental disorder characterized by a disconnection from reality. Psychosis is a group of disorder characterized by thought disorder, abnormal behaviour, defective cognition, delusion and hallucination. Adverse drug reaction is defined as any undesired or unintended effects of drugs treatment. According to the World Health Organization (WHO)- “adverse drug reaction (ADRs) has been defined one which is noxious and unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease, or modification of physiological function”. Adverse drug reactions are the most important causes of the mortality and morbidity. Antipsychotics are the most effective drugs which are used in the psychiatry in the maintenance therapy of mania, psychoses and schizophrenia. The antipsychotics drugs are chemically disparate but have the common property of alleviating the symptoms of organic as well as functional psychosis. But they also have a capacity to cause a wide range of potential adverse drug reactions that can lead to non-compliance that can impair quality of life, may cause the extra pyramidal symptoms which can lead to discontinuation of therapy and in extreme cases it may be fatal. Knowledge of assessment of ADRs due to different antipsychotics is necessary. It helps to choose to safe treatment and reduce the risk of occurrence of ADRs by the clinicians. ADR are often poorly identified and reported in day to day medical practice. As we collect more and more information about ADRs, we need an active surveillance system regarding identification and reporting of ADRs with antipsychotic drugs. On many review articles are read & ward round participation experiences we find that antipsychotic drugs can have shown a various kind of ADRs. Psychiatrist and clinical pharmacist are need to be made aware of these potentially fatal adverse effects associated with antipsychotic drugs via conduction of patients counseling regarding (drugs, disease, doses & side effects), quality-based seminars, published medical literature, conferences, learning programs and health care camps. Keywords: Antipsychotic Drugs, WHO, Adverse Drug Reactions, Pharmacovigilance, Psychiatrist.

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Clozapine-Induced Gastrointestinal Hypomotility: A 22-Year Bi-National Pharmacovigilance Study of Serious or Fatal ‘Slow Gut’ Reactions, and Comparison with International Drug Safety Advice

Cited by 64 publications

References 37 publications

Management of common adverse effects of antipsychotic medications

Management of common adverse effects of antipsychotic medications

A Rational Use of Clozapine Based on Adverse Drug Reactions, Pharmacokinetics, and Clinical Pharmacopsychology

Psychotic Disorders, Definition, Sign and Symptoms, Antipsychotic Drugs, Mechanism of Action, Pharmacokinetics & Pharmacodynamics with Side Effects & Adverse Drug Reactions: Updated Systematic Review Article

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