Low-dose Clozapine Research Articles

Chemogenetic Inhibition of the Amygdala Modulates Emotional Behavior Expression in Infant Rhesus Monkeys.

Manipulation of neuronal activity during the early postnatal period in monkeys has been largely limited to permanent lesion studies, which can be impacted by developmental plasticity leading to reorganization and compensation from other brain structures that can interfere with the interpretations of results. Chemogenetic tools, such as DREADDs (designer receptors exclusively activated by designer drugs), can transiently and reversibly activate or inactivate brain structures, avoiding the pitfalls of permanent lesions to better address important developmental neuroscience questions. We demonstrate that inhibitory DREADDs in the amygdala can be used to manipulate socioemotional behavior in infant monkeys. Two infant rhesus monkeys (1 male, 1 female) received AAV5-hSyn-HA-hM4Di-IRES-mCitrine injections bilaterally in the amygdala at 9 months of age. DREADD activation after systemic administration of either clozapine-N-oxide or low-dose clozapine resulted in decreased freezing and anxiety on the human intruder paradigm and changed the looking patterns on a socioemotional attention eye-tracking task, compared with vehicle administration. The DREADD-induced behaviors were reminiscent of, but not identical to, those seen after permanent amygdala lesions in infant monkeys, such that neonatal lesions produce a more extensive array of behavioral changes in response to the human intruder task that were not seen with DREADD-evoked inhibition of this region. Our results may help support the notion that the more extensive behavior changes seen after early lesions are manifested from brain reorganization that occur after permanent damage. The current study provides a proof of principle that DREADDs can be used in young infant monkeys to transiently and reversibly manipulate behavior.

Rapid-onset supraventricular tachycardia following clozapine initiation and its management with verapamil: a case report

Clozapine is the drug of choice for treatment-resistant schizophrenia. However, the use of clozapine is limited by its serious adverse effects, which often underlie its discontinuation. The cardiovascular side effects that raise safety concerns include tachycardia, myocarditis and cardiomyopathy. The development of clozapine-induced tachycardia is usually observed on higher dosage especially at early stages of treatment. Here, author presented the case of a patient with treatment-resistant schizophrenia who developed asymptotic supraventricular tachycardia despite low dose of clozapine at the second day of treatment. Additionally, author explored the possibility of clozapine re-challenge in combination with verapamil treatment.

A case report of\xa0cholinergic rebound syndrome following abrupt low-dose clozapine discontinuation in a patient with type I bipolar affective disorder

BackgroundRebound cholinergic syndrome is a rare, but well known unwanted phenomenon occurring after abrupt clozapine discontinuation. There have been previous reported cases of cholinergic rebound in the literature; however, these reports described cholinergic rebound following cessation of high doses of clozapine in patients diagnosed with schizophrenia. Here, we report a case of rebound cholinergic syndrome and catatonia in a male patient three days after abrupt discontinuation of 50 mg of clozapine prescribed for type I bipolar affective disorder.Case presentationA 66-year old male of Spanish origin, treated for type I bipolar affective disorder for 15 years and for Crohn disease, was brought to the emergency department because of a sudden onset of mutism, dysphagia and trismus. He was described catatonic and presented hypertension, tachycardia and tachypnea. His body temperature was normal and the laboratory tests were unremarkable at presentation. A head CT and an EEG were in the normal range.While reviewing his history, it appeared the he was on clozapine 50 mg a day, first introduced 2 months ago, during a previous hospitalization for a manic episode resistant to other mood stabilizers. For an unknown reason, the patient’s psychiatrist stopped clozapine three days before the admission and replaced it by risperidone 5 mg and quetiapine 200 mg daily. A cholinergic rebound syndrome was then evoked. The patient’s ability to speak recovered dramatically and fast after the intravenous administration of 2.5 mg of biperiden supporting the diagnosis. Risperidone and quetiapine were also stopped. The patient fully recovered in 20 days after the reintroduction of 50 mg of clozapine and 2.5 mg of biperiden daily.ConclusionsThis case report underscores that cholinergic rebound syndrome may occur in patients suffering from bipolar affective disorders, being on clozapine as a mood stabilizer. The low dose clozapine does not preclude severe manifestations of the phenomenon. Progressive tapering should therefore be adopted in any case.

Behavioral Effects of Acute Systemic Low-Dose Clozapine in Wild-Type Rats: Implications for the Use of DREADDs in Behavioral Neuroscience.

Designer receptors exclusively activated by designer drugs (DREADDs) are popular tools used to manipulate the activity of defined groups of neurons. Recent work has shown that DREADD effects in the brain are most likely not mediated by the proposed ligand clozapine-N-oxide (CNO) but its metabolite clozapine (CLOZ). However, it is not known whether low doses of CLOZ required to activate DREADDs already have DREADD-independent effects on behavior as described for higher CLOZ doses used in previous preclinical studies. To close this gap, we compared effects of acute systemic (i.p.) CLOZ treatment vs. vehicle (VEH) in a wide range of behavioral tests in male wild-type rats. We found that CLOZ doses as low as 0.05–0.1 mg/kg significantly affected locomotion, anxiety and cognitive flexibility but had no effect on working memory or social interaction. These results highlight the need for careful controls in future chemogenetic experiments and show that previous results in studies lacking CNO/CLOZ controls may require critical re-evaluation.

P.1.006 - Chronic administration of clozapine increases the level of serotonin 5-HT1A receptor heterodimerisation with 5-HT2A or D2 receptors in the mouse cortex

Background and Aims It is well established that dopamine D2 receptors and serotonin 5-HT1A and 5-HT2A receptors play an important role in neurotransmission and that alterations in their functioning are implicated in many psychiatric disorders, including schizophrenia. Only since the 1990s has there emerged an appreciation of the effects of atypical antipsychotic medications, which can be beneficial for the negative (cognitive) symptoms via combined action at dopamine as well as serotonin and other classes of neuroreceptors [1]. In recent years, various lines of evidence have revealed the formation of physiologically active GPCR heteromers in the plasma membrane [2,3]. GPCR heteromers offer a novel set of drug targets because the functional association of heteroreceptors, which are partners in the complex, can result in pharmacological and functional properties distinct from those of the monomers (and homomers). Clozapine (CLZ), an antipsychotic drug currently used in the clinic but still being the object of basic studies designed to search for its unique molecular features, has been also shown to act via various heterodimers [4]. Therefore, in the present study, we investigated whether atypical antipsychotic drug, CLZ, and typical drug, haloperidol (HAL), administered to mice acutely or repeatedly affected the formation of heterodimers of dopamine D2–5-HT1A receptors as well as 5-HT1A–5-HT2A receptors in the mouse brain cortex. Materials and Methods Mice C57Bl/6J were treated CLZ in two doses; however, HAL was administered in one dose. In line with our previous behavioral studies, we used ketamine to induce cognitive deficits in mice [5]. To visualize co-localization D2–5-HT1A receptors and 5-HT1A–5-HT2A receptors in the mouse brain immunohistochemistry was used. Proximity ligation assay (PLA) was used to accurately visualize, for the first time, GPCR heterodimers in the native tissue. Data were analyzed using two-way analysis of variance (ANOVA) with Bonferroni post-test to compare all groups of the experiments. Results Our study confirmed the co-localization of D2–5-HT1A and 5-HT1A–5-HT2A receptors in the mouse brain cortex. Low-dose clozapine (0.3 mg/kg) administered repeatedly increased the level of D2–5-HT1A heterodimers in the mouse prefrontal and frontal cortex ([F(2,22)] = 4.630; p Conclusion Our results provide interesting evidence that antipsychotic drugs have effect on the level of D2–5-HT1A as well as 5-HT1A–5-HT2A receptors heterodimerization, which may represent a novel, interesting therapeutic target for many psychiatric disorders.

Repeated Clozapine Increases the Level of Serotonin 5-HT1AR Heterodimerization with 5-HT2A or Dopamine D2 Receptors in the Mouse Cortex.

G-protein–coupled receptor (GPCR) heterodimers are new targets for the treatment of schizophrenia. Dopamine D2 receptors and serotonin 5-HT1A and 5-HT2A receptors play an important role in neurotransmission and have been implicated in many human psychiatric disorders, including schizophrenia. Therefore, in this study, we investigated whether antipsychotic drugs (clozapine (CLZ) and haloperidol (HAL)) affected the formation of heterodimers of D2–5-HT1A receptors as well as 5-HT1A–5-HT2A receptors. Proximity ligation assay (PLA) was used to accurately visualize, for the first time, GPCR heterodimers both at in vitro and ex vivo levels. In line with our previous behavioral studies, we used ketamine to induce cognitive deficits in mice. Our study confirmed the co-localization of D2/5-HT1A and 5-HT1A/5-HT2A receptors in the mouse cortex. Low-dose CLZ (0.3 mg/kg) administered repeatedly, but not CLZ at 1 mg/kg, increased the level of D2–5-HT1A and 5-HT1A–5-HT2A heterodimers in the mouse prefrontal and frontal cortex. On the other hand, HAL decreased the level of GPCR heterodimers. Ketamine affected the formation of 5-HT1A–5-HT2A, but not D2–5-HT1A, heterodimers.

The Utilization of Low-Dose Clozapine as Mono-Therapy in the Treatment of Recurrent Catatonia: A Case Report

The Utilization of Low-Dose Clozapine as Mono-Therapy in the Treatment of Recurrent Catatonia: A Case Report

Clozapine dose for schizophrenia.

Clozapine dose for schizophrenia.

Sex Differences in Psychiatric Hospitalizations of Individuals With Psychotic Disorders

We aimed to evaluate the association between sex and hospitalization characteristics in psychotic disorders. We identified all acute hospitalizations, between 2010 and 2013, for psychotic disorders in patients younger than 45 and older than 55 years (n = 5411) in the hospital's database. In addition, we identified patients who were prescribed with intramuscular risperidone (n = 280) or clozapine (n = 192) at discharge. The results showed that women younger than 45 years had lower proportions of hospitalizations (33.52% vs. 66.47%) and involuntary hospitalizations (33.85% vs. 45.55%) than did men in the same age group. Women older than 55 years had higher proportions of hospitalizations (57.22% vs. 42.77%) and similar proportion of involuntary hospitalizations. Women younger than 45 years were prescribed similar doses of intramuscular risperidone and lower doses of clozapine (345.8 vs. 380.2 mg) and women older than 55 years were prescribed higher doses of intramuscular risperidone (44.8 vs. 34.4 mg/2 weeks) and clozapine (164.32 vs. 154.5 mg) than were men in the same age group. Women in the reproductive years have better hospitalization characteristics than do men on these measures.

New insights in the pharmacotherapy of psychosis: The example of Parkinson's disease psychosis

IntroductionWith 10 million of patients across the world, Parkinson's disease is the second most common form of neurodegeneration, after Alzheimer's. Among half of patients develop psychotic symptoms, such as visual hallucinations and delusions, which are correlated with higher rate of placement in nursing home, are difficult to treat and severely affect quality of life, making Parkinson's disease psychosis (PDP) a major public health issue.ObjectivesThe aim of this study is to identify treatment options that could be used to treat PDP and clarify underlying pathophysiology.MethodWe conducted a literature review on Pubmed, Goggle scholar and Cochrane library, using a combination of the following: “Parkinson's disease Psychosis” “visual hallucinations” “Pimavanserin” “Clozapine” “atypical anti-psychotics” 120 articles were screened.ResultsConsidering that hallucinations arise from overactivation of dopaminergic receptors, treatment options include reducing the dopaminergic drugs used to control motor symptoms; using atypical anti-psychotics such as Risperidone, Olanzapine, Quetiapine, which often results in the worsening of extra-pyramidal symptoms. Another option is the use of low doses of Clozapine, which has been proven efficient with no worsening of non-motor symptoms, suggesting the implication of other pathways, such as serotonin. Finally, Pimavanserin, a 5-HT2A receptor inverse agonist, without any dopaminergic activity, has been demonstrated to be effective in the treatment of PDP, well tolerated and easy to use.ConclusionSerotonin inverse agonists represent a major breakthrough in the pharmacotherapy of PDP, and may lead the way to changes in the treatment of schizophrenia and other psychotic disorders.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Translational Value of Drug Discrimination with Typical and Atypical Antipsychotic Drugs.

This chapter focuses on the translational value of drug discrimination as a preclinical assay for drug development. In particular, the importance of two factors, i.e., training dose and species, for drug discrimination studies with the atypical antipsychotic clozapine is examined. Serotonin receptors appear to be an important pharmacological mechanism mediating clozapine's discriminative cue in both rats and mice, although differences are clearly evident as antagonism of cholinergic muscarinic receptors is important in rats at a higher training dose (5.0mg/kg) of clozapine, but not at a lower training dose (1.25mg/kg). Antagonism of α1 adrenoceptors is a sufficient mechanism in C57BL/6 and 129S2 mice to mimic clozapine's cue, but not in DBA/2 and B6129S mice, and only produces partial substitution in low-dose clozapine discrimination in rats. Dopamine antagonism produces partial substitution for clozapine in DBA/2, 129S2, and B6129S mice, but not in C57BL/6 mice, and partial substitution is seen with D4 antagonism in low-dose clozapine drug discrimination in rats. Thus, it is evident that clozapine has a complex mixture of receptor contributions towards its discriminative cue based on the data from the four mouse strains that have been tested that is similar to the results from rat studies. A further examination of antipsychotic stimulus properties in humans, particularly in patients with schizophrenia, would go far in evaluating the translational value of the drug discrimination paradigm for antipsychotic drugs.

Atypical neuroleptic malignant syndrome in adolescence

Objective To report re-challenges of antipsychotic drugs after neuroleptic malignant syndrome (NMS) in a case of Cotard syndrome and considering electroconvulsive treatment as an option in these cases. Case report A 17-year-old adolescent, treated for acute psychotic attack with multi-antipsychotic (olanzapine, risperidone) for 15 days, developed NMS within 48hours of the addition of low doses of clozapine to his regimen. Symptoms included fever, agitation, dysautonomia, pulmonary edema, ventricular failure and laboratory findings, which included elevation of CK levels, leukocytes, transaminase, resolved after discontinuation of psychotropics, supportive management and 6 days of treatment with bromocriptine and amantadine. At first, patient was treated with low doses of quetiapine. Then, we decided to imply ECT because of two reasons. The first reason is low dosage of quetiapine was not believed to control symptoms which included Cotard syndrome based on assertions such as I am dead, I cannot breathe, My teeth and my bones are melted, suicidal thoughts, incoherence speech. The second reason is increasing quetiapine dose rapidly could have caused relapsing of NMS. Finally, we transferred our patient to another child psychiatry clinic where ECT can be applied. Discussion Starting atypical antipsychotic drugs in re-emergence of post NMS psychosis and catatonia is a challenge. Because of the risk of relapsing NMS, anti-psychotic drugs must be started lower dosage, titrated up slowly then patient should be monitored at least two weeks until resumption of therapy. Process of monitoring depends on existing of clinical residua. Moreover, it is unclear when clinical residua exist, thus it is difficult to interpret the existing guidelines on safe reintroduction of antipsychotics. At that point, ECT can be considered as an option in order to control psychotic symptoms. Conclusions Clinicians should closely monitor patients when restarting anti-psychotic drugs after NMS owing to risk of relapsing NMS and ECT should be considered as an option in order to control symptoms.

Severe eosinophilia with relative neutropenia associated with low dose clozapine therapy

Severe eosinophilia with relative neutropenia associated with low dose clozapine therapy

Clozapine toxicity due to a multiple drug interaction: a case report

IntroductionWe report the case of a multiple drug interaction involving clozapine, antifungals and oral contraceptives, which resulted in an increased clozapine plasma level, pericarditis with pericardial effusion and eosinophilia in a young Caucasian woman. These symptoms and signs disappeared a few days after discontinuation of clozapine. At present, we are not aware of reports of clozapine–antifungals interaction, whereas there is only one other case report on the interaction between oral contraceptives and clozapine. The purpose of this case report is to show the risk of potentially serious adverse effects stemming from drug interactions involving medications routinely used in clinical practice.Case presentationA 29-year-old Caucasian woman diagnosed with a schizoaffective disorder was admitted to a psychiatric unit for acute psychosis (hallucinations, delusions and catatonic behavior). She denied smoking tobacco products and was on long-term oral contraceptives. During the first month of hospitalization she was treated with antipsychotics and for 1 week she took simultaneously fluconazole and miconazole gel, after being diagnosed with oral candidiasis. On the last day of antifungals treatment, 29 days after admission, clozapine was started with resolution of psychotic symptoms. After 3 weeks, her clozapine plasma level had increased to 542ng/mL and eosinophilia was observed. She complained of nausea, vomiting and palpitations; echocardiography showed echocardiographic abnormalities and pericardial effusion. Oral contraceptives were discontinued and after 1 week clozapine was interrupted, with a complete resolution of side effects and pericardial effusion within 4 days.ConclusionsClozapine is metabolized by cytochrome P450. The use of inhibitors or other substrates of cytochrome P450, such as antifungals and oral contraceptives, can cause long-lasting interactions and clozapine toxicity. The Naranjo algorithm shows clozapine is a definite cause of pericarditis (score 9) and both clozapine–antifungals and clozapine–contraceptives interactions resulted probable (score 5) in Drug Interaction Probability Scale. A good knowledge on drugs that act as substrates, inhibitors or inducers of cytochrome P450 is mandatory. When those drugs are used in patients taking clozapine, blood level monitoring of clozapine should be recommended, since a lower dose of clozapine might be required to prevent clozapine toxicity.

Low Dose Celecoxib Combined with Clozapine for Treatment of Schizophrenia: A Double Blind Randomized Clinical Trial

Introduction: Higher levels of pro-inflammatory cytokines in schizophrenia have suggested that dysfunctions of the immune system may play a role in this disabling condition. The current study was performed to discover if low dose celecoxib combined with clozapine may improve symptoms of schizophrenia or not. Methods: In a double-blind randomized clinical trial, 40 patients with non- treatment resistance schizophrenia were allocated into two groups. The experimental group received flexible and low dose clozapine plus 200 mg/day of celecoxib for 4 weeks, while the control group received clozapine plus placebo. Experimental and control groups were similar in terms of age, gender, clozapine mean dosage and severity of schizophrenic symptoms at baseline. Main outcomes were severity of schizophrenia symptoms measured by the Positive and Negative Syndrome Scale (PANSS) at baseline followed by the second and fourth weeks. Results: Although both groups experienced significant improvement in all PANSS sub-scales in the second and fourth weeks (P 0.05). Conclusion: Our findings did not support the findings of prior studies that report a significant effect for celecoxib combined with atypical antipsychotics. Such inconsistency may be due to statistical power, drug interactions between clozapine and celecoxib, and the low dose of celecoxib used in this study. Future research is needed on the role of anti-inflammatory medications as adds-on treatments for schizophrenia. Keywords: Celecoxib, Clozapine, Schizophrenia, Randomized Controlled Trial

Treatment of Catatonia Using Low Doses of Clozapine

Catatonia is a state of apparent unresponsiveness to external stimuli in a person who is apparently awake and which occurs in children, adolescents, and adults and is characterized by a variety of symptoms and signs of impairment of the expression of voluntary thoughts and movements. Antipsychotics should be used with care as they can worsen catatonia and are the cause of neuroleptic malignant syndrome, a dangerous condition that can mimic catatonia and requires immediate discontinuation of the antipsychotic. The use of atypical antipsychotics to treat catatonia remains anecdotal, owing to concerns that they may worsen catatonic symptoms. We describe the case of good treatment response in low doses of clozapine in a adolescent with first psychotic episode –catatonic feature.

Low-Dose Clozapine for an Adolescent with TBI-Related Fregoli Delusions

regoli delusion, first described by Courbon and Fail in 1927, named after an Italian actor Leopoldo Fregoli, is a rare delusional misidentification syndrome which entails that different people are in fact the same person in disguise who is able to change their appearance [1]. It is commonly linked to schizophrenia, schizoaffective disorder, and other organic brain syndromes including head trauma, ischaemic strokes, AD, Parkinson’s disease, epilepsy or metabolic derangements [2]. Neurologically, it represents a disconnectivity syndrome of hyperidentification (cf. Capgras) [3]. As TBI sequelae, psychotic symptoms may occur early or late [4]. In the early postinjury period, psychotic symptoms are most commonly manifestations of post-traumatic delirium. In the late postinjury period, these symptoms may be either part of a schizophrenia-like psychosis, comprising predominantly persecutory delusions, auditory hallucinations and dearth of negative symptoms, or be associated features of a mood disorder. The best available epidemiological evidence suggests that TBI confers a modest increased risk for schizophrenia-like psychosis especially if coupled with a positive family history of psychosis and male gender [5]. TBI renders patients more susceptible to neurologic side effects of antipsychotics [6].Here, we are reporting an adolescent with TBI that later on developed Fregoli delusions. He had supersensitivity to multiple antipsychotic trials with no response at all. When shifted to low-dose clozapine, delusions entirely remitted with great tolerability. A 15-year-old Palestinian youngster was casualty petitioned in accompaniment of his parents for paranoid ideations of 3 months duration. He is the youngest of 3 sibs emanating from nonconsanguenious monogamous family with no genetic load of neuropsychiatric disorders. Unremarkable developmental trajectories. Distinguished scholastic achievement. No history of smoking or illicit drug use. No medical comorbidities. Had a history of MVA, 10 months ago, incurred severe TBI, admitt ed to ICU, discharged on prophylactic Valproate 1000 mg/d for posttraumatic seizures. He was faring well following this accident, as reported by parents, apart from occasional complaints of low-grade headaches and giddiness. Lately, he started to voice out non-sensical talk that the man who hit him by the car is disguising and morphing in the bodies of neighbours, doorkeeper and servants, stalking him in order to kill him. He was panic-stricken by the idea. Fragmented sleep. Lost appetite. Dropped from school attainment. He was seen by a private psychiatrist, a diagnosis of psychotic depression was entertained, and fluoxetine (Prozac

Treatment of refractory substance-induced psychosis in adolescent males with a genetic predisposition to mental illness

This article presents two cases of adolescent males who were admitted to our inpatient psychiatric unit with a psychotic, disorganized presentation. Both males had a genetic vulnerability to mental illness and reported significant substance use. Their symptoms were refractory to treatment and required the use of clozapine. Both patients experienced significant side effects, which limited the maximum daily dose of clozapine. However, they responded to a dose that was much lower than that typically used in adults. There is significant evidence in the literature about cannabis use triggering psychotic breaks in vulnerable individuals. We speculate that substance use (including synthetic cannabinoids) triggers treatment-resistant psychosis that requires the use of clozapine. Further, lower doses of clozapine may be sufficient to treat the substance-induced psychotic symptoms than those typically used in adult schizophrenia.

On the Discovery and Development of Pimavanserin: A Novel Drug Candidate for Parkinson’s Psychosis

Parkinson’s disease psychosis (PDP) is a condition that may develop in up to 60 % of Parkinson’s patients, and is a major reason for nursing home placement for those affected. There are no FDA approved drugs for PDP but low doses of atypical anti-psychotic drugs (APDs) are commonly prescribed off-label. Only low-dose clozapine has shown efficacy in randomized controlled trials, but all APDs have black box warnings related to the increased mortality and morbidity when used in elderly demented patients. Using molecular pharmacological profiling of a large collection of marketed drugs, we discovered that potent inverse agonist activity against 5-HT2A serotonin receptors was a common feature of atypical APDs, especially the atypical APDs used to treat PDP. Since low-dose clozapine therapy selectively blocks this receptor, it was hypothesized that a highly selective 5-HT2A receptor inverse agonist might provide good symptom control in patients suffering from PDP, with a greatly improved safety and tolerability profile. A high throughput screening and subsequent chemical lead optimization campaign to develop potent, selective 5-HT2A receptor inverse agonists was launched, eventually resulting in the discovery of pimavanserin. Pimavanserin displays nanomolar potency as a 5-HT2A receptor inverse agonist, selectivity for 5-HT2A over 5-HT2C receptors, and no meaningful activity at any other G-protein coupled receptor. It demonstrated robust activity in preclinical models of schizophrenia and PDP, and did not worsen motoric symptoms, in contrast to the APDs tested. In a Phase III clinical trial, pimavanserin showed highly significant benefits in the primary endpoint, the scale for assessment of positive symptoms-PD, a scale adapted for use in PDP. In addition, improvements in all other efficacy endpoints, including physician’s clinical global impression, caregiver burden, night-time sleep quality and daytime wakefulness, were seen. Pimavanserin demonstrated good safety and tolerability and did not worsen motoric symptoms as assessed by the unified Parkinson’s disease rating scale parts II and III. An open-label extension study has further demonstrated that pimavanserin is safe and well-tolerated with long-term use. Pimavanserin may therefore offer a viable treatment option for patients suffering from PDP.

Reintroduction of Clozapine After Perforation of the Large Intestine—A Case Report and Review of the Literature

To report on a patient who was successfully rechallenged with clozapine after perforation of the large intestine and pulmonary embolism post operatively, and provide a literature review on clozapine rechallenge. A 46-year-old Japanese man with treatment-resistant schizophrenia developed constipation and slight abdominal discomfort while taking clozapine 275 mg/day. He developed appendicitis, leading to perforation of the large intestine. During the postsurgery period, a partial embolism of the pulmonary artery was revealed. The patient's constipation was relieved when clozapine was discontinued, but other antipsychotics failed to control his delusions well. After thorough discussion, it was decided to rechallenge with clozapine. The low dose of clozapine 200 mg/day was tolerable for his delusion, and his constipation was managed with laxatives and exercises until 8 months after the accident. Clozapine is a gold standard medication in treatment-resistant schizophrenia but is associated with various adverse effects, some of which are life-threatening. Reintroduction of clozapine after severe adverse drug effects when other medications are not effective almost always poses a clinical dilemma for mental health professionals. A PubMed search (to January 25, 2013) using the key words clozapine and rechallenge found 50 articles. There were only sporadic positive case reports regarding the rechallenge after clozapine-related serious gastrointestinal problems. From the currently available evidence, most psychiatrists appear to avoid reintroduction of clozapine. However, the evidence is too weak to draw a definitive conclusion about reintroduction of this drug. Reintroduction of clozapine after initial adverse effects in patients with treatment-resistant schizophrenia may warrant case-by-case judgment, but needs to be further investigated.